Stress mediates the activation of a variety of systems ranging from inflammatory to behavioral responses. In this review we focus on two neuropeptide systems, corticotropin-releasing factor (CRF) and arginine vasopressin (AVP), and their roles in regulating stress responses. Both peptides have been demonstrated to be involved in anxiogenic and depressive effects, actions mediated in part through their regulation of the hypothalamic-pituitary-adrenal axis and the release of adrenocorticotropic hormone. Because of the depressive effects of CRF and AVP, drugs modifying the stress-associated detrimental actions of CRF and AVP are under development, particularly drugs antagonizing CRF and AVP receptors for therapy in depression.