Neuroimaging studies of major depression have identified neurophysiological abnormalities in multiple areas of the prefrontal cortex (PFC), the amygdala, and related parts of the striatum and thalamus. Some of these abnormalities are mood state-dependent, and appear in regions where cerebral blood flow (CBF) increases during other normal and pathological emotional states. These neurophysiological differences between depressives and non-depressed controls may thus locate areas where physiological activity changes to mediate or respond to the emotional, behavioral and cognitive manifestations of major depressive episodes (MDE). Other abnormalities persist following symptom remission, and are found in orbital and medial PFC areas where post mortem studies demonstrate reductions in cortex volume and/or histopathological changes in primary mood disorders. These orbital and medial PFC areas have been shown by other types of evidence to modulate emotional behavior and stress responses, suggesting that dysfunction involving these regions may be involved in the pathogenesis of depressive symptoms. Finally, physiological activity is decreased during MDE in dorsal PFC areas implicated in language, selective attention, visuospatial or mnemonic processing, but these abnormalities reverse with symptom remission. These areas of 'deactivation' during the depressed state may reflect neurophysiological interactions between cognitive and emotional processing, and may relate to the subtle cognitive impairments associated with MDE.