Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because reduced protein turnover leads to bulk intracellular protein accumulation. However, conditions associated with compromised UPS function are also associated with impairments in protein synthesis, and impairment of UPS function is sufficient to inhibit protein synthesis. These data suggest that the toxicity of UPS inhibition need not depend on gross intracellular protein accumulation, and indicate the potential for crosstalk between the UPS and protein-synthesis pathways. In this review, we discuss evidence for interplay between the UPS and protein-synthesis machinery, and outline the implications of this crosstalk for physiological and pathological processes in the CNS.