Increasing genetic, pathological, and experimental evidence suggest that neurodegeneration in both familial and sporadic forms of Parkinson's disease (PD) may be related to a defect in the capacity of the ubiquitin-proteasome system (UPS) to clear unwanted proteins, resulting in protein accumulation, aggregation, and cytotoxicity. This concept is supported by in vitro and in vivo laboratory experiments which show that inhibition of UPS function can cause neurodegeneration coupled with the formation of Lewy body-like inclusions. This hypothesis could account for the presence of protein aggregates and Lewy bodies in PD, the other biochemical features seen in the disorder, and the age-related vulnerability of the substantia nigra pars compacta. It also suggests novel targets for putative neuroprotective therapies for PD.