Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder of uncertain aetiology, presenting with autonomic failure, variably combined with parkinsonism, cerebellar dysfunction, and pyramidal signs. The pathological process affects striatonigral, olivopontocerebellar and central autonomic systems. Depending on the respective involvement of these neuroanatomical structures two major clinical phenotypes are distinguishable, namely striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). However, the neuropathological lesions are not exclusively limited to the structures mentioned above, but may involve other parts of the central, peripheral, and autonomic nervous systems as well and this indicates  the multi-system character of MSA. The core histological feature of MSA is the presence of glial cytoplasmic inclusions (GCI, Papp-Lantos bodies) within oligodendroglia cells containing mis-folded α-synuclein (αSyn). The presence of GCIs is a required feature for the post-mortem diagnosis of definite MSA. As shown by studies using animal models, the pathogenesis of MSA is characterised by several processes, in addition to αSyn mis-folding, including oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids and impairment of oligodendrocyte progenitor cells. Although the basic mechanisms of αSyn-triggered gliopathy are not fully understood, neuron-to-oligodendrocyte transfer of αSyn and ‘prion-like’ spreading of synucleinopathy inducing oligodendroglial and myelin dysfunction are associated with chronic neuroinflammation. In addition to glial inclusions, neuronal pathology is suggested to play an important role in the development and progression of MSA. The combination of these mechanisms is finally leading to a system-specific pattern of neurodegeneration, which may act as an emerging template for cause-directed and disease-modifying therapies of MSA.