Mediators of neuroendocrine and autonomic function seem to play important roles in the core symptoms of major depression. Although centrally directed corticotropin-releasing hormones and norepinephrine contribute to core symptoms such as alterations in anxiety, arousal, and mood, they also exert significant potentially clinically relevant effects on key processes that proceed in the periphery. Thus, the core clinical manifestations of major depression may represent a fraction of a complicated systemic illness that not only influences thought and feeling, but also the processes involved in premature cardiovascular disease, osteoporosis, and premature death. Subdividing patients with major depression into meaningful biologic subgroups will facilitate the elucidation of the mechanisms that underlie the central and peripheral manifestations of major depressive illness.