In Parkinson’s disease (PD), in addition to degeneration of the nigrostriatal dopaminergic pathway, a variety of neuronal systems are involved, causing multiple neuromediator dysfunctions that account for the complex patterns of functional deficits. Degeneration affects the dopaminergic mesocorticolimbic system, the noradrenergic locus ceruleus (oral parts) and motor vagal nucleus, the serotonergic raphe nuclei, the cholinergic nucleus basalis of Meynert, pedunculopontine nucleus pars compacta, Westphal-Edinger nucleus, and many peptidergic brainstem nuclei. Cell losses in subcortical projection nuclei range from 30 to 90% of controls; they are more severe in depressed and demented PD patients. Most of the lesions are region-specific, affecting not all neurons containing a specific transmitter or harboring Lewy bodies. In contrast to Alzheimer’s disease (AD), subcortical system lesions in Parkinson’s disease appear not to be related to cortical pathology, suggesting independent or concomitant degeneration. The pathogenesis of multiple-system changes contributing to chemical pathology and clinical course of Parkinson’s disease are unknown.