Diurnal changes in plasma corticosterone concentrations of rats are supposed to be controlled by low amplitude changes in plasma adrenocorticotropin (ACTH) that run in phase with marked changes in adrenal sensitivity to ACTH (1, 2). These sensitivity changes are probably under neuronal control (3), but the mechanisms remain to be elucidated. By the use of a highly specific monoclonal antibody to rat corticotropin-releasing factor (CRF) (4), we studied the role of endogenous CR- in these processes. Blockade of endogenous CRF prevented the evening rise in plasma ACTH and reduced corticosterone levels to less than 10%. The CRF antibody did not affect morning ACTH concentrations but nevertheless reduced morning corticosterone levels by 40% to 60%. In dexamethasone-treated rats, immunoneutralization of endogenous CRF caused a similar reduction in the plasma corticosterone response to exogenous ACTH. We conclude that endogenous CRF plays a physiological role in controlling the adrenal sensitivity to ACTH.