The influence of β-endorphin on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro was studied. β-Endorphin (10<sup>–11</sup>–10<sup>–10</sup> M) caused dose-related increases in the CRF contents of the hypothalami and of the medium in which they were incubated. Its effects were antagonized by naloxone (10<sup>–8</sup>–10<sup>–7</sup> M). In contrast, in higher concentrations (10<sup>–7</sup>–10<sup>–5</sup> M), it reduced, in a dose-dependent manner, both the spontaneous release of CRF from the hypothalami and the release which normally occurred in response to acetylcholine, 5-hydroxytryptamine, morphine, met-enkephalin and leu-enkephalin. The inhibition of CRF release was associated with a rise in the tissue content of the hormone and was not blocked readily by naloxone. The results support the concept that opioid substances may be involved in the control of hypothalamo-pituitary-adrenocortical function.