The HPA axis is the principal effector of the generalized stress response and crucial for maintaining basal and stress-related homeostasis. There has been an exponential increase in knowledge regarding the interactions among the elements of the HPA axis (CRH, AVP, ACTH, glucocorticoids) and between the HPA axis and the other components of the stress system (locus ceruleus/norepinephrine-sympathetic systems), as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of HPA axis dysfunction, characterized by sustained hyperactivity or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders or susceptibility to such disorders.