Cells of the immune system have recently been recognized as a source of the proopiomelanocortin (POMC)-derived peptides, ACTH and endorphins, and their receptors. In this review, the nature of the immunoregulatory and hypothalamic signals which elicit the production of these leukocyte-derived hormones is discussed. Further, comparisons are made between the various proteolytic processing patterns of POMC in leukocytes as compared with those observed in the hypothalamus and anterior or intermediate lobes of the pituitary gland. The possible functioning of leukocyte-derived ACTH and endorphins as well as their pituitary counterparts in a complete regulatory loop between the neuroendocrine and immune systems is described.