Introduction Synucleinopathies are a group of neurodegenerative disorders sharing in common the presence of intracellular fibrillar inclusions composed of polymerized α-synuclein (α-syn). Although the biological function of this presynaptic protein remains largely unknown, overwhelming evidence indicates that its self-aggregation in neurons and/or oligodendrocytes is associated with the impairment of nervous system function and cellular demise leading to disease. Pathological inclusions composed of α-syn have been the focus of enumerable clinical and pathological studies with the earliest dating almost to the beginning of the twentieth century. However, the finding that these inclusions are comprised of α-syn only became apparent in the past 5 years following the identification of a mutation in the α-syn gene in families with Parkinson's disease. α-Syn inclusions are the defining characteristics of several disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, they are also found in a significant percentage of other neurodegenerative disorders including neurodegeneration with brain iron accumulation type-1 (NBIA-1), Down's syndrome, and familial and sporadic Alzheimer's disease (AD) (Table 15.1). The understanding of the role of α-syn in neurodegenerative disease requires the determination of the normal function and properties of this protein, the clinicopathological assessment of the relationship between α-syn inclusions and disease, and the elucidation of the mechanism of pathogenesis. In this chapter, we will focus on the most recent developments in these aspects of synucleinopathies, but the description of these diseases also requires an overview of the most significant features that have been documented for over almost 100 years.