Proteasome-mediated protein degradation is responsible for a large percentage of bulk protein turnover, particularly the degradation of short-lived and oxidized proteins. Increasing evidence suggests that proteasome inhibition occurs during the aging of the central nervous system (CNS), and in a variety of age-related disorders of the CNS. The focus of this review is to discuss the role of the proteasome as a regulator of oxidative stress, with preservation of proteasome function playing an important role in preventing oxidative stress, and proteasome inhibition playing an important role as a mediator of oxidative stress. In particular, this review will describe experimental evidence that proteasome inhibition is sufficient to induce mitochondrial dysfunction, increase reactive oxygen species generation, elevate RNA and DNA oxidation, and promote protein oxidation. Taken together, these data indicate that the proteasome is an important regulator of oxidative damage in the CNS, and suggest that proteasome inhibition may serve as an important switch for the induction of oxidative stress in the CNS. Additionally we discuss the likelihood that the 20S proteasome and 26S proteasome may play different roles in regulating oxidative stress and neurotoxicity in the aging CNS, and in age-related disorders of the CNS.