Corticotropin-releasing factor (CRF) and the related urocortin peptides mediate behavioral, cognitive, autonomic, neuroendocrine and immunologic responses to aversive stimuli by activating CRF(1) or CRF(2) receptors in the central nervous system and anterior pituitary. Markers of hyperactive central CRF systems, including CRF hypersecretion and abnormal hypothalamic-pituitary-adrenal axis functioning, have been identified in subpopulations of patients with anxiety, stress and depressive disorders. Because CRF receptors are rapidly desensitized in the presence of high agonist concentrations, CRF hypersecretion alone may be insufficient to account for the enhanced CRF neurotransmission observed in these patients. Concomitant dysregulation of mechanisms stringently controlling magnitude and duration of CRF receptor signaling also may contribute to this phenomenon. While it is well established that the CRF(1) receptor mediates many anxiety- and depression-like behaviors as well as HPA axis stress responses, CRF(2) receptor functions are not well understood at present. One hypothesis holds that CRF(1) receptor activation initiates fear and anxiety-like responses, while CRF(2) receptor activation re-establishes homeostasis by counteracting the aversive effects of CRF(1) receptor signaling. An alternative hypothesis posits that CRF(1) and CRF(2) receptors contribute to opposite defensive modes, with CRF(1) receptors mediating active defensive responses triggered by escapable stressors, and CRF(2) receptors mediating anxiety- and depression-like responses induced by inescapable, uncontrollable stressors. CRF(1) receptor antagonists are being developed as novel treatments for affective and stress disorders. If it is confirmed that the CRF(2) receptor contributes importantly to anxiety and depression, the development of small molecule CRF(2) receptor antagonists would be therapeutically useful.