The perception of Parkinson’s disease (PD) as a disease centered on dopaminergic striatonigral neurodegeneration has changed fundamentally since 1997 when the first mutation in the SNCA gene (PARK1) encoding a-synuclein was discovered (Polymeropoulos et al. 1997). This discovery formed the basis for a new description of brain pathology characterized by the presence of a-synuclein aggregates in brain cell inclusions that are the hallmarks of PD and other synucleinopathies: dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). This field has been thoroughly covered by many reviews during the last decade (Gai et al. 1998; Spillantini and Goedert 2000; Huang et al. 2004; Ubhi et al. 2011). This review will briefly highlight the historical breakthroughs but focus on a-synuclein modifications, human neuropathology, biomarker potential, current animal models and the new concepts emerging after the significance of extracellular a-synuclein has gained support.