The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is a master regulator of central and peripheral stress responses required to restore and maintain homeostasis. PACAP modulates the hypothalamic-pituitary-adrenal (HPA) axis in response to acute psychogenic but not systemic stressors, through activation of corticotropin-releasing hormone (CRH) release to drive adrenal corticosterone (CORT) output. During direct high-frequency stimulation of the splanchnic nerve that is designed to mimic stress, PACAP regulates adrenomedullary catecholamine secretion. In addition to transmission, PACAP simultaneously facilitates the biosynthesis of adrenomedullary catecholamines through stimulus-secretion-synthesis coupling. During periods of chronic psychogenic stress, PACAP-mediated CORT elevation fails to desensitize and contributes to the development of maladaptive behaviors such as anxiety and depression. Based on these findings, PACAP regulates not only adaptive responses to stress but also maladaptive responses to sustained psychological stress. PACAP receptor antagonists could have therapeutic relevance in preventing hyperactivity of the HPA axis and offering protection against chronic stress-associated anxiety and depression.