Classic Parkinson's disease (PD) is characterized by fibrillar α-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, α-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the α-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying α-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative α-synucleinopathies.