Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variably associated extrapyramidal signs and symptoms, is virtually always accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and gliosis in the substantia nigra at autopsy. Neuronal loss is particularly marked in the ventrolateral cell groups of the substantia nigra, which project to the putamen via the nigrostriatal pathway. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule-binding protein tau. In idiopathic Parkinson's disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons, as well as neurons in the peripheral autonomic nervous system. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is an accumulation of α-synuclein within glial cytoplasmic inclusions (GCIs). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia.