Parkinson's disease (PD) is the second most common neurodegenerative diseases, which occurs in both inheritable and sporadic forms. The interplay of the genetic mutations and environmental exposure to disease risk factors contributes to the pathogenic events leading to the demise of dopaminergic neurons in PD. Proteasome is one of the major proteolytic machinery responsible for degrading unwanted and damaged intracellular proteins. Emerging evidence implicates the incomplete proteolysis by ubiquitin-proteasome system (UPS) in PD pathogenesis. Proteasome inhibition recapitulates some of the key features of PD in vivo and in vitro. Varieties of dopaminergic neurotoxins emerge to inhibit proteasomal function. Given that some PD-related gene mutations impair proteolytic function of UPS, it has been well-accepted that both genetic and environmental factors may conspire to compromise the UPS in the initiation and progression of the disease. The enzymatic assays for the proteasomal activities with fluorogenic substrates and western blot analysis of ubiquitinated proteins provide an entry point to determine UPS function in the process of dopaminergic degeneration.