The heterogeneity of major depression suggests that multiple neurocircuits and neurochemicals are involved in its pathogenesis. Anhedonia and psychomotor symptoms are, however, particularly characteristic features of major depression and may provide insights into its underlying psychobiology. Importantly, these symptoms appear to be mediated by dopaminergic mesolimbic and mesostriatal projections, the function of which is, in turn, influenced by key gene variants and environment stressors. Indeed, there is growing evidence of the way in which the dopaminergic system is associated with cognitive-affective disturbances in depression, and provides a useful target for therapeutic interventions. At the same time, a range of other systems are likely to contribute to the psychobiology of this condition.