In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa.