After a few days grinding them out I have finished the challenges and am here to offer up some advice for what to look for and how to straight up break most of the challenges on the list. This should be some solid advice if you are having trouble with them. This is my first guide so leave a comment and let me know what you think!

There are a few challenges that can be pretty difficult. Newer players should start with Slow Roll, and Computer Savvy as they are the easiest. Suicide King, Cat Got Your Tongue, Solar System, Family Man, Beans and Demo Man are by far the most difficult so tackle those accordingly to your ability.

As far as cheesing the challenges, as long as you have some patience, you can get off to an amazing start with enough time just holding 'R' and waiting for a curse room to be adjacent to your starting room. They can give you spirit hearts, Goat Head, Guppy Items, and with Guppy's Head can give you some amazing offensive power with challenges where you are blindfolded and can't shoot. Red chests can also teleport you to the devil room, where Mom's Knife, Brimstone, Dark Bum, Damage Upgrades, Flight and familiars await you... You know the drill, but getting anything like that on the first floor can make your run so much faster and less of a hassle if you are having trouble doing it legit.

Another thing to look out for that can help a lot is The Bible. If you don't have another spacebar item that you prefer this can save you a lot of heartache on Mom and It Lives as it kills them in one shot. A lot of the challenges end on either of these boss fights so that reduces the difficulty to just reaching these fights then actually completing them. The passive flight can be helpful too on tough rooms. The Bible can be found most commonly in the shop, or in a black market. Black markets can be found hidden under rocks so if you have the bombs, it never hurts to check.

Blank card also breaks the game with Sharp Plug, 48 Hour Energy/Hematamesis and the deck of cards so always visit shops if you have the money. Teleport cards are good options too for skipping chunks of the floor or stealing an item from the boss rush/trap rooms.

Another thing I have noticed is that with the challenges that require you to beat Isaac, the devil rooms after mom's heart can contain items rather then the trap door, so always check it if you get it. It seems that if there is only a light leading up to the Cathedral that is the time when there will be items in the devil room if you get it. Be mindful of your goal though, don't accidentally go down to Sheol if the goal has already been met or requires you to go to the cathedral.

Goal: Mom

Reward: Rune of Hagalaz

This challenge is one of two challenges that allow item rooms, so you have a huge advantage here. Cheesing this challenge really isn't necessary but resetting until you get item room and curse room adjacent to the starting room will let you know quickly if you can get the best possible start. If you are having trouble seeing crank up the gamma to make it easier on yourself.

Passives to look for: Just treat this like your normal runs and pick what you feel comfortable with.

Recommended spacebar item: Head of Krampus, Prayer Card

Items that break this run: Black Candle, Brimstone, Mom's Knife, Dark Bum

Goal: Mom

Reward: Rune of Jera

The one annoying thing about this challenge is the fact you have Number 1 and have no range at all, which will come to haunt you with rooms that have enemies over gaps. Prioritize Range Ups or try finding an item that takes range out of the equation like technology.

Passives to look for: Mom's Underwear/Lipstick/Heels, Flight

Items to avoid: Dead Onion

Recommended spacebar Item: Flush is ok but long recharge time and ineffectiveness against bosses and some other enemies makes it marked for replacement asap. Book of Belial or health generating items like The Nail are good choices.

Items that break this run: Range Ups, Brimstone, Mom's Knife, Flight, Long Range Familiars.

Goal: Mom

Reward: Rune of Ehwaz

This challenge is interesting. Very low damage to start with makes a lot of rooms and bosses a grind. Massive knockback can be an issue as well. The confusion status can be awkward with jumping enemies too so pay attention to that so you don't dodge into where they are jumping. If you notice a jumping enemy being confused stay in your general area as that will be the safest place. Small diagonal dodges are good if there are other non-confused jumping enemies around.

Passives to look for: Damage ups! (Blood Clot, Mark, Pact, Magic Mushroom, Growth Hormones, Synthol, Polyphemus etc. Death's Touch is funny too)

Items to avoid: Technology, Thin Odd Mushroom, Number 1, Ludovico Technique, Proptosis.

Items that break this run: Brimstone, Mom's Knife, Fetus Items.

Goal: Satan

Reward: Rune of Dagaz

This is the first challenge on the list that is actually a challenge. Having to go all the way to Satan can make this more of a chore, especially dying on Sheol as it can eat up a fair bit of time. ♥♥♥♥♥ of Babylon is very useful here and using a starting curse room to boost your damage, find Goat Head and get some spirit hearts as well as put yourself in the curse state can help a lot. If you are confident, use Sacrificial Dagger to do some serious damage.

If you accidentally ruin your curse of babylon state, if you come across a blood bank you can hit it and run out of the room before it pays out to get yourself down to 1 red heart if needed. It is much more benificial to be in the curse state as Eve as it seems to give a bigger damage bonus then to other characters.

Passives to look for: Mom's Contacts are an excellent synergy with Sacrificial Dagger. Other then that the usual stuff, Damage and Health are always important.

Recommended spacebar item: Crystal Ball, Invincibility Items, Satanic Bible or The Nail are excellent choices as well.

Items that break this run: Guppy's Paw is amazing for this run, letting you stay in curse state without worry of ruining it as well as doing what it usually does. Other then that another run that can be broken with Brimstone or Mom's Knife.

Goal: Mom

Reward: Rune of Ansuz

Man this run feels like a grind too. I hate runs with low speed, but that is a personal preference. Depending on Infamy to block shots will ultimately get you killed. I would prioritize finding flight sooner then later because mobility is key in this challenge. Also take the time to break every rock you see (unless they are bomb rocks :P) as tinted rocks provide a good source of health and finding a black market or hidden zelda room is always helpful.

Passives to look for: Speed Ups! (Lord of the Pit, Speed Ball, Roid Rage, Growth Hormones, Belt, Spoon) Damage is important too.

Recommended spacebar item: Yum Heart is honestly a decent spacebar item to start with if you take damage too much. Finding Goat head in your first curse room will negate the penalty of no devil rooms for red heart damage so if you roll with Yum Heart make this a priority and hope for flight on floor 2. Other then that Invincibility items can be very nice too.

Items to avoid: Samsons' Chains, Fat Odd Mushroom,

Items that break this run: Flight, Brimstone, Mom's Knife, Holy Mantle

Goal: Mom's Heart

Reward: Rune of Perthro

Here we go now things are getting interesting. You aren't going to be able to break this challenge with conventional means like brimstone or mom's knife as being blindfolded prevents the most common overpowered setups. Thankfully you do have a decent amount of protection as well as the defensive benefit of flight. The whole crux of this challenge is learning how to use the various orbitals to dish out damage while at the same time dodging can be difficult. Regular room clearing is going to be the most problematic part of the challenge. Bosses are mostly about identifying when they remain stationary and rotating clockwise around them to keep Forever Alone in their hitbox. Bosses like Steven, Blighted Ovum, Gurdy Jr, The Fallen, Mask of Infamy, and Carrion Queen might give you trouble though. Finding more orbitals or replacing pretty flies with better ones is a good idea. Also if you end up with more money then you know what to do with and have a 3 skull monty at your disposal you can generate as many friendly flys as you want by loosing as they will turn friendly. It is somewhat annoying though since you need to be fast to keep them away from each other since they can be killed when they spawn if they don't have time to turn friendly.

Passives to look for: Cube of Meat/Ball of Bandages, Sacrificial Dagger, Big Fan, Guillotine, ???'s Only Friend, BBF, BFF's, Best Bud, Hive Mind, Smart Fly, Holy Mantle, any other familiar, any damage ups to increase friendly fly damage
Recommended spacebar item: Guppy's Head or Book of Revelations. Invincibility items combined with damaging orbitals are real nice too. Head of Krampus is always a good choice too.

Items to avoid: It's important to remember that the usual breaking items won't work here, don't see brimstone in the devil deal and pay 2 hearts for it thinking it will save you. Any tear effect or stat up regarding tear speed, rate or range won't help you.

Items that break this run: None really, Guppy's Head combined with the 9 Volt can give you an edge if you have a safe spot in rooms for infinite fly generation. Cube of Meat type orbitals do a LOT of rapid damage so invincibility items or cards combined with it can kill any boss rapidly. Could be good to roll with Book of Revelations until you get second level meat boy/girl and then switch to book of shadows or similar if given the opportunity.

Goal: Isaac

Reward: Suicide King

Yes you heard right, this challenge goes all the way to Isaac and is in my opinion either THE hardest or second hardest challenge on the list if attempted legit. Some people will say it is easy you just need to get used to how my reflection and ipecac works. This is true to an extent but in practice just feels very awkward and difficult to perfect on a room by room basis. Your accuracy must be spot on in order to negate the my reflection BS imposed on you. It seems to be the shadow of the tear must come in contact with the shadow of the enemy to make a direct hit. Always be cautious of rocks and walls in the room to not blow yourself up. Another tip I have heard is to fire in one direction and move in the opposite to have the shot land in the direction you fired (at least I think) I can't really articulate a proper strategy in words for you. I just suggest to practice in the start room to get used to it. Either that or restart until you get teleported to the devil room and pay 2 hearts for Mom's Knife

Passives to look for: HP! (You are gunna need it!) Range and shot speed can help too, Orbitals, Broken Watch can be a blessing or a curse. 9 Lives can be a benefit if gotten early enough. Holy Mantle or Dark Bum are a godsend too (on any run :P)

Recommended spacebar item: Any health regen item, Guppy's Head is real nice too and can carry you almost all the way to mom but loses it's luster past then. Head of Krampus especially paired with the battery is probably the best offensive choice, an overcharged Head of Krampus can kill any boss outright and take Issac to <50%

Items to avoid: Tammy's Head, Any tear rate up (unless you are real confident) I'm not sure how Anti-Grav tears work with this it may improve or break your run so that's something left to be tested. I also don't know if Brimstone overrides ipecac or not hopefully someone can let me know.

Items that break this run: Mom's Knife, Dark Bum, Guppy's Paw, Flight. Pyromaniac along with a lot of red health is a game winner here too.

Goal: Mom

Reward: Rune of Alzir

This one is very similar to Solar System and many of the same tactics apply. Not really a breakable run but its over at mom so it is easier then solar system. The fact that you are guppy already makes any familiar you can get even more powerful as they will spawn flies for you. Even Brother Bobby can be an asset on floor 1. The fact you start with Guppy's Head is nice too, look for damage ups and the head can carry you most of the way. Some people say that the hairball is powerful and easy to use but I call BS on that. I get hit way to much trying to use it offensively as the mechanics of it are sloppy and hard to aim at the same time feeling inconsistent. Maybe you will end up good with it and if that's the case then great since that will make this challenge a cakewalk.

Passives to look for: Any Familiar, Orbitals including Guillotine, Damage Ups, Speed ups can help if using the hairball. Holy Mantle/Dark Bum.

Recommended spacebar item: Guppy's Head is just fine and can be used all the way to the end. But the usual suspects work just fine here too; Head of Krampus, HP regen items etc.
Items to avoid: Brimstone, Mom's Knife, Any tear effect/rate/speed/range

Items that break this run: Offensive orbitals combined with invincibility items, Dark Bum, Lil Brimstone

Goal: Mom's Heart

Reward: The Chaos Card

Man, what a disappointing run. This very well may be your first encounter with Dr Fetus in rebirth and you will quickly understand how nerfed it was. Bomb's apparently scale with your damage now so you will be struggling at the start to clear rooms. Bosses seem to take more damage then regular mobs in this challenge so room clearing is the tough part. That is, if you actually want to do the room clearing. The nice thing about Dr. Fetus is you can skip every room that isn't a miniboss or prior to the actual boss. Most of the time it is just fine to skip through every room, kiting enemies around while you wait for the door to open. You won't get consumables this way but they won't give you much of an advantage in this run anyway. If you can get a good start and pick up the mark and or flight then you can get the consumables you need from secret rooms, tinted rocks, and mushrooms. Get enough money for a lucky compass and then it turns into a rush for the bosses at that point. If you come across a door in a regular room that seems to not open with bombing then skip it, as you seemingly can't bomb into a miniboss room from the adjacent room either.

Passives to look for: Damage Ups! HP is very important too so hopefully you will get them from your bosses. Bomb Synergy is a good choice and Holy Mantle is real nice for any mistakes you may make.

Recommended spacebar item: Guppy's Head again comes in as a nice choice for room clearing if needed. Head of Krampus again is always a nice choice. (sounding like a broken record :P)

Items to avoid: Tear rate up is bad in this challenge. Fast tears means you will shoot another bomb before the first has a chance to reach it's destination making the second bomb bounce back towards you! This can get out of control fast, even with only 1 tears up so watch out for that. If you do take a tears up, even in the form of an all stats up then pay attention and try not to fire consecutively in a line. Bob and Weave Tom, Bob and Weave. Nothing except Epic Fetus will override Dr. Fetus so stay away from Mom's Knife and Brimstone. Familiars are a mixed bag too, I wouldn't recommend them since aiming them will distract you from your fetus shots. Anti Grav tears are a bad choice too. I don't even know if Ludovico Technique does anything with fetus items so I would stay away from that too if somehow you could even find it. (Boss trap rooms?)

Items that break this run: Epic Fetus, Dark Bum, Spirit of the Night. Pyromaniac with a lot of red health again will break this run too.

Goal: Mom

Reward: Credit Card

This run is interesting. Every room is a curse room but you have the map and compass as well as the yum heart to compensate. You also have access to Treasure rooms so first floor Holy Mantle is a possibility and that straight up breaks this run. Goat Head is another possibility that removes red heart damage penalties from the equation. Treat this run just like Pitch Black and you will get it done. Not too tough. The reward for this challenge is incredibly useful, it is a one time use card that will make all items in a room free of cost, including the shop, devil deal, and black market so completing this challenge first may be of great help to your other challenge progress.

Passives to look for: If you want to risk the trip to the Treasure rooms then choose whatever you feel is a decent start.

Recommended spacebar item: Yum Heart is an ok choice and is doable from the beginning. Especially with Goat Head. All the other main OP spacebars are a good choice here too, Book of Belial, Head of Krampus, HP generation, Invincibility etc.

Items to avoid: Teleportation items, Cursed Eye, other potential sources of damage (BBF)

Items that break this run: Holy Mantle negates the entire challenge and is possible to get on floor 1. I'm not sure how flight interacts with this challenge, it is always a good choice regardless.

Goal: Isaac / Satan

Reward: Rules Card

This challenge is all about starting OP with low health, if you can stack health up you won't have a problem. Epic Fetus seems to be just as powerful as it was in vanilla. This is another run where you can skip all normal rooms by bombing the doors too so you can knock this challenge out real quick as long as you get some kind of HP generation or good boss drops. It seems whatever faith/evil affinity you have by the time you get to mom's heart will determine if you go to Isaac or Satan. In my opinion Satan is easier and more likely because devil deals are where it's at for me. You may differ though so be prepared for Isaac if you go that route. Along the way make sure to go to every secret room, blow up all the rocks/skulls/mushrooms for health and items and you will be set. It is a little tricky when Loki's Horns proc as they can spin around and confuse your dodges and get you hit, but doesn't take a lot to get used to.

Passives to look for: HP! Orbitals are always nice, Bomb Synergy,Flight.

Recommended spacebar item: The usual suspects again; Head of Krampus, Guppy's Head, HP generation, Invincibility.

Items to avoid: Brimstone, Mom's Knife, any tear effect.

Items that break this run: HP really is the only thing you are going to need. Dark Bum will win this outright on it's own. Pyromaniac again will break it too.

Goal: Mom

Reward: A Card Against Humanity

I think this challenge is here just to prove the point that lemon mishap is a viable item now. It can do boatloads of damage. Can be tricky to use properly but it is completely doable to beat this run with what's given at the start. Of course you can replace lemon mishap with something stronger and it will be even easier. Head of Krampus shines with the 9 volt here. Not a tough one.

Passives to look for: HP, Damage, Orbitals, Flight.

Recommended spacebar item: Head of Krampus, The Nail, Lemon Mishap

Items to avoid: Nothing really

Items that break this run: Brimstone, Mom's Knife, Cool Tear effects. Dark Bum.

Goal: Mom

Reward: Burnt Penny

This was a tough one for me. Another run where you are blindfolded and can't shoot. You have Pyro so room skipping is a good idea, but choosing the wrong path can make you run out of bombs real quick. Having the Treasure Map or Compass can be a life saver here. Learning how to push the bombs in boss fights and timing jumping enemies so they take damage against the bomb is the key here. Orbitals or The Bible can make a huge difference for the final fight too, as you may be running low on bombs towards the end. Replace the bean as soon as possible, it is worthless, does little damage and recharges way to slow to be useful. I replaced mine with the Nail for a while then Head of Krampus later and killed mom with a cube of meat.

Passives to look for: HP, Orbitals, Bomb Synergy, Flight.

Recommended spacebar item: Head of Krampus again.

Items to avoid: Brimstone, Mom's Knife, Tear effects.

Items that break this run: Pyromaniac. Compass and Map are game changers too so you know where to go.

Goal: Mom

Reward: SMB Super Fan

This run can go fast if RNG is on your side. A couple Emperor Cards can make short work of this challenge. You can also restart repeatedly until you get a joker, it seemed faster then actually checking the curse rooms, but they are worth checking too. This challenge isn't too tough as long as you get decent boss items and some proper devil rooms.

Passives to look for: Damage ups, Tear effects, Orbitals, Flight.

Recommended spacebar item: Head of Krampus takes the cake again if you don't want to risk the RNG with the cards. Nail, Book of Belial, Invincibility items are nice too.

Items to avoid: None really. Personal choice as always

Items that break this run: Blank card with 48 hour energy, Hematamesis/Fanny Pack and Sharp Plug will straight up break the game with the tarot cards, so have fun if that is an option. Every other regular breaking item will work too, Brimstone, Knife etc.

Goal: Mom

Reward: Swallowed Penny

The fact this "challenge" goes to mom is a joke. You start overpowered and with piercing shots. The My Reflection hook is hardly a downside when your tears are 1/2 the size of the screen. This is a good introductory challenge for people to knock one off the list. Once you try it you will understand.

Passives to look for: Any

Recommended spacebar item: Any

Items to avoid: Proptosis

Items that break this run: It's pretty much already broken. If you need to restart for a first floor devil deal then you just aren't ready for the rest of the list. Play some Azazel for a while and get your dodging skills up.

Goal: Mom

Reward: Robo-Baby 2.0

Another challenge that is very lackluster in the "challenge" aspect. Double technology and homing just wrecks everything. I think this challenge is on the list to demo the synergy of laser type tear effects and homing. It is super neat and fun to use though so you will be impressed with the technical prowess of this challenge. This is another good introductory challenge.

Passives to look for: Damage is always nice, you might need HP too depending on how careless you get. Tear effects can make you even more OP.
Recommended spacebar item: Hp Generation like The Nail or Satanic Bible are a good choice.

Items to avoid: I think Ludovico Technique breaks this run (in a bad way) I might be wrong though.
Items that break this run: Brimstone or the knife will seal the deal here.

Goal: Mom

Reward: Death's Touch

This challenge has a neat mechanic. It aims to make you turn every room into pac man. Any enemy that chases you down will be easy. Fast moving enemies on the other hand may be annoying. Strange attractor has a good name because it does make enemies move strangely and can have unexpected results resulting in damage. Overall this run isn't too difficult. It could use some damage upgrades though because the anti-grav tears make hitting some enemies difficult if you aren't use to it. After a little while you will get the hang of it and the fact it only goes to mom is a blessing.

Passives to look for: Tears up, Damage up, all the regular stuff.

Recommended spacebar item: Another run where Head of Krampus will straight up win it for you.

Items to avoid: Anything you don't prefer with anti-grav. Brimstone is weird with it. The knife is still usable.

Items that break this run: The knife is a solid choice again if you are having trouble. Death's Touch is really neat with this challenge too. It's too bad that you unlock it in the first place with this challenge, but if you ever replay it then its a good choice.

Goal: Mom

Reward: Technology 0.5

This run is all about being guppy without flight. It is only to mom, so it's not too tough. Getting a good RNG roll and getting luck up in your rotation can make the mulligan really strong here. I only played this one one time and beat it on my first try and haven't experimented with it further. Just prioritize damage and flight like most other challenges and you will do fine.

Passives to look for: Damage ups, HP ups, Tear Rate, PHD

Recommended spacebar item: Guppy's Head again is a nice synergy that fits with the challenge. Apart from that any choice that you can find is nice.

Items to avoid: None

Items that break this run: Luck up pills, Guppy Transformation, Brimstone, Knife.

Goal: Isaac

Reward: Epic Fetus

Here is my other contender for the toughest challenge in the game. Another one where you can't shoot and cheese with brimstone or the knife. You only get rotten baby, brother bobby, and sister maggy for offense in this one. Rotten baby with damage upgrades is a great item and can almost win it for you. I think your best chance is to go for full guppy and get the fly generation to the max while holding the paw. That's how I won this challenge. It is a tough one though so expect some restarts and some devastating losses against Isaac.

Passives to look for: Guppy Items, Familiars, Speed and Damage Ups, HP ups, Orbitals.

Recommended spacebar item: In an ideal situation you will get Guppy's Head on floor 1 and carry it until the mom fight gathering red heart containers and then get the Paw.

Items to avoid: Brimstone, Knife, any tear effect/rate/speed/range

Items that break this run: Like mentioned above, the Guppy transformation while holding the paw with enough familiars to spawn flies is enough to win it for you. Lil' Brimstone or Dark Bum are nice too.

Goal: Mom's Heart

Reward: Rune of Berkano

Ah the old favorite from Wrath of the Lamb. It has been made much easier by being nerfed down to the heart instead of going to Isaac. It can also be broken like most of the other challenges with brimstone or the knife. If you can do most of the other challenges on this list and pull some lucky boss items or a good first deal with the devil/curse room you will be set. Not much else to say about this one I would imagine it is in the middle in terms of difficulty.

Passives to look for: Anything you can get your hands on that holds your preference.

Recommended spacebar item: Any, but The Bible can make it even easier.

Items to avoid: Your Preference

Items that break this run: All the regular stuff, Brimstone, The knife, Flight, Dark Bum, Holy Mantle. You know the drill. Chances are unless you are an amazing player you are going to need at least 1 good devil deal to secure the win. With a few Damage Ups, HP, Tear rate and flight this run will be over before you know it.

I know a lot of this seemed like a broken record. Most of the challenges can be broken by the same things that broke the game in WoTL. This is the problem with no treasure rooms, being stuck with Devil Deals for the majority of your power ties your hands a bit.

Always blow up mushrooms when you can as Magic Mushroom is amazing and can appear out of them. If there ever is an opportunity to get into the item room pool then enjoy any synergy you can muster as a lot of these challenges will feel samey if you are aiming at breaking them. Other then that always give it a fair shake and see if you can beat them legit as some of them are quite fun and challenging with only boss items or natural devil deals.

The usefulness of utility items like The Compass, Treasure Map, Broken Watch, Blank Card, PHD, BFF's and others can't be overstated. Always pick these up if you have the keys and money as they can save you a lot of damage and time in the long run. Another item to look for in the shop is the Converter. In conjunction with Guppy's Paw this gives you an opportunity to get 11 red hearts by alternating using the paw and the converter. After getting 11 red hearts, hold the paw for the rest of the run and you have 33 Soul hearts in reserve after loosing the 11 you have, so a total of 44 hearts can carry you through even the toughest of challenges. Or if you have a sun card, finding The Blank Card in the shop is a game winner too, especially with the Habbit. If you have more then 4 red hearts and the Habbit, The Blank Card in conjunction with the sun card makes you invincible. Just be careful to never hit 'Q'!

In quite a few of the challenge sections I recommend passives that seem like they may be unobtainable given the no treasure room aspect of most of the challenges. Granted they are less common, but you have the ability to get any treasure room item early on by coming across a random pedestal item in a room, (common on the basement but requires flight) challenge or boss trap rooms or via a hidden black market or zelda type treasure room. So if you are holding R trying to break the challenges, on spawns that don't have a curse room adjacent to your starting room it can be beneficial to go into the closest adjacent room anyway to try for one of these options. Treasure room items are much less common in challenges, but not out of the question.

Other non-gameplay related advice is to not burn yourself out on a tough challenge. If you are having trouble, go back to the regular game and practice some more on the floor you were having trouble with in the challenge. Get used to the map generation mechanics so you can read floors better. Or just plain go play another game if you are getting burned out. Nothing builds resentment like a huge string of failures so take a break and come back to it with a fresh look on things and everything will work out. Patience is key with a lot of runs, don't rush it that's when you will take dumb damage. Challenge runs are not about getting to the boss rush so you have infinite time to mess around and extort the floor out of as much items and consumables as you can. You never know if that skull is going to have a black heart in it or a mushroom with magic mush so do everything you can if you are struggling.

Thanks for reading if you are still here! Leave a comment and let me know how to improve the guide or let me know what you liked about it!