Functional brain imaging techniques, which permit noninvasive measures of neurophysiology and neuroreceptor binding, are powerful and sensitive tools for research aimed at elucidating the pathophysiology of major depression. The application of these technologies in depression research has produced several studies of resting cerebral blood flow (BF) and glucose metabolism in subjects imaged during various phases of illness and treatment. This review examines these data and the principles relevant to their interpretation and discusses the insights they provide into the anatomical correlates of depression. Within the anatomical networks implicated in emotional processing by other types of evidence, these BF and metabolic data demonstrate that major depression is associated with reversible, mood state-dependent, neurophysiological abnormalities in some structures and irreversible, trait-like abnormalities in other structures. In some of the regions in which trait-like abnormalities appear, abnormal metabolic activity appears at least partly related to the anatomical abnormalities identified in magnetic resonance imaging (MRI) studies of depression.