Using an in vivo CRF assay, extra-hypothalamic CRF activity was demonstrated in the peripheral blood of rats bearing extensive ventral hypothalamic lesions. The rats had been hypophysectomized and subjected to laparotomy stress 5 h earlier. CRF activity was not detected in lesioned or lesioned and hypophysectomized animals not subjected to laparotomy stress. CRF activity was assessed by the increment in plasma corticosterone levels produced in the lesioned recipient animals after administration of blood from donor animals. Blood containing CRF activity was ineffective in recipient animals that were both lesioned and hypophysectomized. A direct pituitary CRF action was further demonstrated by the effectiveness of intrapituitary injections of 0.8 µ\ plasma from laparotomy stressed lesioned and hypophysectomized donors. Comparison was made of the time-courses of response to the presumed extra-hypothalamic CRF and the CRF of median eminence origin (ME-CRF). Blood from hypophysectomized rats, containing ME-CRF, elicited an immediate but relatively transient secretion of steroid in the recipient animal, whereas the extra-hypothalamic CRF produced, in addition to the immediate effect, a prolonged elevation of considerable magnitude. Based upon its extreme potency and prolonged time-course of action, the term tissue-CRF was proposed to distinguish it from ME-CRF of hypothalamic origin. Tissue-CRF may be released