Functional brain imaging studies suggest that prefrontal and anterior paralimbic components of basal ganglia-thalamocortical circuits have altered function in bipolar depression. Abnormal anterior cortical activity is a common finding in not only bipolar, but also unipolar and secondary depression. In addition, increases in subcortical anterior paralimbic activity may occur in bipolar and unipolar depression, consistent with corticolimbic dysregulation. Variability in findings may be related to differences in methodology, patterns of depressive symptoms, illness subtypes, medications, and treatment responses. Emerging data are beginning to reveal specific biochemical disturbances in prefrontal and anterior paralimbic components of basal ganglia-thalamocortical circuits in bipolar and unipolar disorders. These include changes in serotonergic and dopaminergic neurotransmission, in N-acetyl aspartate, choline, gamma-aminobutyric acid, and glutamate, phospholipid concentrations, and in high energy phosphate metabolism. Although functional brain imaging studies have advanced our knowledge of the neurobiology of bipolar depression, it remains to be established whether clinical applications will develop to facilitate diagnosis and more effectively target treatments. Published by Elsevier Science B.V.