Alterations in cellular structure and synapse composition are central to proper nervous system function. Recent work has identified the ubiquitin-proteasome system (UPS) as a key regulator of neuronal biology. The UPS is essential for the growth and development of immature neurons and is a critical mediator of synaptic adaptability in mature neurons. Furthermore, proteinaceous deposits that accumulate in diverse neurodegenerative disorders are enriched in components of the UPS, suggesting that UPS dysfunction may be pivotal for pathogenesis. Here, we summarize existing knowledge about the role of the UPS in brain function, highlighting recent work delineating its importance in neuronal development, plasticity, and degeneration.