The prohormone pro-opiomelanocortin (POMC) is cleaved posttranslationally into the biologically active peptides ACTH, -endorphin, and -melano-cyte-stimulating hormone (-MSH). Although thesepeptides were first thought to be exclusively of pituitary origin, there are now many studies showing that POMC peptides can also be produced by cells of the immune system, including T cells, B cells, and monocytes. The identity between pituitary and leukocyte POMC peptides has been established. The synthesis of POMC peptides in the immune system canbe modulated by immunostimulants, corticotropin-releasing hormone (CRH), IL-1, and glucocorticoids.The data suggest that the type of POMC stimulus may determine the cell type involved, processing pathway, and ultimately the specific peptide produced which can influence immune function. POMC peptides have both stimulatory and inhibitory actions in vitro which may influence all the major immune cell types, particularly T cells. In vivo, POMC peptides produced by cells of the immune system may act in an endocrine fashion at the adrenal gland and in the neuroendocrine system. They may also play an essential role in pain control. Thus, POMC peptides produced by cells of the immune system may function as endogenous regulators within the immune system as well as conveyors of signals from the immune system to other target tissues including the neuroendocrine system.