This talk will bring a Mind-Body perspective to remarkable advances in our understanding of the neurobiology of major depression. Specifically, we will review data suggesting that depressive disorders may be best understood as conditions of central nervous system and peripheral danger system hyperactivity. Consistent with this notion, imaging studies of depressed patients show a pattern of increased activity in limbic and paralimbic brain regions involved in threat appraisal and stress system activation, with reversal of these abnormalities upon successful treatment. Depression doesn't just affect the brain, however, and many studies now show that the condition is typically characterized by a pattern of glucocorticoid insufficiency, sympathetic hyperactivity, vagal withdrawal and inflammatory activation. These bodily alterations are, in turn, capable of producing changes in brain functioning common to depression--thus closing the mind-body loop. This talk will conclude with a discussion of the diagnostic and prognostic implications of this emerging mind-body paradigm