Oxidative stress occurs in a variety of disease settings and is strongly linked to the development of neuron death and neuronal dysfunction. Cells are equipped with numerous pathways to prevent the genesis, as well as the consequences, of oxidative stress in the brain. In this review we discuss the various forms and sources of oxidative stress in the brain and briefly discuss some of the complexities in detecting the presence of oxidative stress. We then focus the review on the interplay between the diverse cellular proteolytic pathways and their roles in regulating oxidative stress in the brain. Additionally, we discuss the involvement of protein synthesis in regulating the downstream effects of oxidative stress. Together, these components of the review demonstrate that the removal of damaged proteins by effective proteolysis and the synthesis of new and protective proteins are vital in the preservation of brain homeostasis during periods of increased levels of reactive oxygen species. Last, studies from our laboratory and others have demonstrated that protein synthesis is intricately linked to the rates of protein degradation, with impairment of protein degradation sufficient to decrease the rates of protein synthesis, which has important implications for successfully responding to periods of oxidative stress. Specific neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and stroke, are discussed in this context. Taken together, these findings add to our understanding of how oxidative stress is effectively managed in the healthy brain and help elucidate how impairments in proteolysis and/or protein synthesis contribute to the development of neurodegeneration and neuronal dysfunction in a variety of clinical settings.