Leptin, the product of the obesity gene (ob) predominantly secreted from adipocytes, plays a major role in the negative control of feeding and acts via a specific receptor (Ob-R), six isoforms of which are known at present. Evidence has been accumulated that leptin, like other peptides involved in the central regulation of food intake, controls the function of the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches. Leptin, along with Ob-R, is expressed in the hypothalamus and pituitary gland, where it modulates corticotropin-releasing hormone and ACTH secretion, probably acting in an autocrine-paracrine manner. Only Ob-R is expressed in the adrenal gland, thereby making it likely that leptin affects it by acting as a circulating hormone. Although in vitro and in vivo findings could suggest a glucocorticoid secretagogue action in the rat, the bulk of evidence indicates that leptin inhibits steroid-hormone secretion from the adrenal cortex. In keeping with this, leptin was found to dampen the HPA axis response to many kinds of stress. In contrast, leptin enhances catecolamine release from the adrenal medulla. This observation suggests that leptin activates the sympathoadrenal axis and does not appear to agree with its above-mentioned antistress action. Leptin and/or Ob-R are also expressed in pituitary and adrenal tumors, but little is known about the role of this cytokine in the pathophysiology.