Among the more consistent observations in patients with major depression is dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis presenting as elevation of basal cortisol, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropin-releasing factor (CRF), and a blunted adrenocorticotropic hormone (ACTH) response to challenge with exogenous CRF. These features appear to be state, rather than trait markers, and are normalized upon successful treatment. These pathophysiologic adaptations may arise from defects in central drive to the neuroendocrine hypothalamus, disruption of normal adrenocortical hormone receptor function or a modification of HPA axis function at any level. Functional assessment of the HPA axis is thought to provide a window into central nervous system operation that may be of diagnostic value in this and other affective disorders regardless of whether CRF and glucocorticoids are directly involved in the origin of major depression or merely exacerbate the consequences of other primary defects.