The influence of morphine and enkephalins on the functional activity of the hypothalamo-pituitary-adrenocortical system in the rat was studied by investigating their effects on the secretion in vivo and in vitro of corticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing factor (CRF) by the hypothalamus. A single injection of morphine caused a rise followed by a fall in hypothalamic CRF content and increases in the concentrations of ACTH in the plasma and adenohypophysis. In addition, the stress-induced increments in hypothalamic CRF and pituitary and plasma ACTH were exaggerated in morphine-treated rats. The production of ACTH by pituitary segments in vitro was not affected by the addition to the incubation medium of morphine, met-enkephalin, leu-enkephalin or naloxone. However, morphine and the enkephalins stimulated the secretion of CRF by isolated hypothalami and their effects were antagonized by naloxone. The results indicate that morphine and the enkephalins evoke hypothalamo-pituitary-adrenocortical activity by stimulating specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRF.