The hypothalamic-pituitary-adrenal (HPA) axis is the core endocrine stress system in humans. While corticotropin-releasing hormone (CRH) and vasopressin are the major secretagogue peptides of the HPA axis/stress system, glucocorticoids play a pivotal feedback role in the regulation of the HPA axis. Both the peak and the nadir in circulating cortisol concentrations are elevated in depression, but overall there is little reduction in amplitude of the circadian rhythm and neither is its timing signifycantly shifted. CRH has been administered following pretreatment with dexamethasone, which results in augmented adreno corticotropic hormone and cortisol responses in depressed patients compared to normal controls. Studies have also shown that women who were sexually or physically abused in childhood exhibit a markedly enhanced activation of the HPA axis. To date, most large-scale studies of compounds targeting the HPA axis have produced disappointing results. Whether or not the HPA axis is an appropriate target for novel antidepressants has yet to be convincingly demonstrated.