The mesotelencephalic dopamine (DA) system is heterogeneous with respect to nuclei, terminal loci, DA receptor subtypes, electrophysiological characteristics and response patterns, and neuropharmacological response to a range of agents. The majority of mesocortical and mesolimbic DA neurons originate in the ventral tegmental area. Mesostriatal DA neurons originate in substantia nigra pars compacta. DA neurons originating from the retrorubal field primarily innervate subcortical limbic and neostriatal loci. Mesostriatal terminal loci have relatively low densities of D3 and D4 receptors, compared to mesolimbic and mesocortical loci. The D1 and D2 receptors appear more homogeneously distributed. Electrophysiologically, mesostriatal DA neurons show more regularity in firing pattern (fewer bursting events), and a lower basal firing rate than mesolimbic or mesocortical neurons. Neuropharmacologically, mesocortical DA neurons are less responsive to intravenous d-amphetamine, (+)apomorphine, and chronic antipsychotic drug treatment. Mesocortical DA neurons are also relatively insensitive to iontophoretically applied DA, a finding congruent with their reported relative lack of somatodendritic autoreceptors. Neurochemically, mesoaccumbens DA neurons are more sensitive to systemic administration of drugs with addictive liability.