Parkinson’s disease (PD) is a complex neurodegenerative disorder that involves a constellation of motor and nonmotor symptoms. Although several medications are moderately effective in attenuating motor symptoms during the early stages of PD, there are currently no therapies available to slow the underlying neurodegeneration, in large part because the molecular underpinnings of the disease are incompletely understood. In this chapter, we review neuropathological, toxicological, and genetic data supporting the premise that mitochondrial dysfunction and autophagic impairment play a central role in PD pathogenesis. Moreover, we examine findings suggesting that the interplay between these two toxic phenomena contributes to neurodegeneration in the brains of PD patients. Finally, we discuss how insights into the roles of mitochondrial and autophagic impairment in PD can set the stage for developing disease-modifying therapies.