Significance: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of a wide variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. The most significant risk factor for the development of these disorders is aging, which is associated with a progressive decline in UPS activity and the accumulation of oxidatively modified proteins. To date, no therapies have been developed that can specifically up-regulate this system. Recent Advances: In the neurodegenerative brain, dysfunction of the UPS has been associated with the deposition of ubiquitinated protein aggregates and widespread disruption of the proteostasis network. Recent research has identified further evidence of impairment in substrate ubiquitination and proteasomal degradation, which could contribute to the loss of cellular proteostasis in neurodegenerative disease. Novel strategies for activation of the UPS by genetic manipulation and treatment with synthetic compounds have also recently been identified. Critical Issues: Here, we discuss the specific roles of the UPS in the healthy central nervous system and establish how dysfunctional components can contribute to neurotoxicity in the context of disease. Future Directions: Knowledge of the UPS components that are specifically or preferentially involved in neurodegenerative disease will be critical in the development of targeted therapies which aim at limiting the accumulation of misfolded proteins without gross disturbance of this major proteolytic pathway. Antioxid. Redox Signal. 21, 2302–2321.