Corticotropin-releasing factor (CRF) is the major regulator of the hypothalamic-pituitary-adrenal (HPA) axis, and plays a key role in coordinating the endocrine, as well as autonomic and behavioral responses of an organism to stress. Direct CNS administration of CRF to laboratory animals produces an aggregate of effects that mimic the mammalian stress response. Impeding CRF function with CNS administration of a peptidergic CRF antagonist can block these manifestations of the stress response whether produced by exogenous CRF or occurring naturally in response to a stressor. A role for hypersecretion of CRF in the pathophysiology of depression is suggested by the finding that CNS administration of CRF mirrors many of the signs and symptoms utilized as diagnostic criteria for major depression. In addition, a large body of clinical evidence points to excess hypothalamic secretion of CRF and an accompanying HPA axis hyperactivity in patients with major depression. The recent development of selective, small molecule CRF(1) receptor antagonists, which block the effects of CRF both in vitro and in vivo, suggest that these compounds may be effective in the treatment of affective and anxiety disorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models. Copyright 2001 John Wiley & Sons, Ltd.