Our understanding of neuronal cell biology in the last 10 years has exploded. In parallel, our grasp of basic cellular processes, such as protein synthesis and protein degradation has also grown exponentially. In this review, we provide an in-depth background to details of current knowledge of the Ub/proteasome pathway. We also provide examples of recent experiments in neurobiology that suggest a central role for targeted protein degradation by the Ub/proteasome pathway to ensure proper neuronal function. From the examples provided, it is clear the activity of the proteasome is required for neuronal pathfinding during development, regulation of synaptic branching and number, and synaptic plasticity. We conclude with a discussion of how defects in proteasome pathway function may lead to neuronal dysfunction, with specific emphasis on diseases characterized by the accumulation of ubiquitin (Ub)-positive inclusions. Our goal is to excite the expert neurobiologist to the myriad ways that specific neuronal functions could be regulated (or dysregulated) by mechanisms involving the Ub/proteasome pathway.