Central and peripheral humoral responses of the adrenocortical system were measured for 2 h after the application of several stimuli. Two min after the onset of the stressesof shamadrenalectomy or laparotomy with intestinal traction there was a 4-6-fold increase inhypothalamic CRF content as compared to control content. This is the usual CRF response to stress. In contrast, after adrenalectomy or manipulation of the pedicles of adrenal glands, CRF content at 2 min was only slightly increased above baseline values. This finding suggests that touching the adrenal vascular and nervous supply results in a direct neural input to the hypothalamus that is qualitatively different from most other stimuli. At times later than 2 min after stress, when plasma corticosterone levels rise in the intact rat, the patterns of CRF and ACTH responses that were observed after adrenalectomy were determined by whether corticosterone replacement therapy was given. Without corticosterone replacement, the CRF and ACTH responses to adrenalectomy resembled those of laparotomy with intestinal traction. When corticosterone was administered 2 and 40 min after adrenalectomy, the CRF and ACTH responses resembled those of sham-adrenalectomy. At 20 min, CRF content was low after laparotomy with intestinal traction or adrenalectomy and high after sham-adrenalectomy or adrenalectomy with corticosterone replacement. Plasma ACTH peaked by 20 min, and remained high for 2 h after the first stimuli, and was significantly decreased from the 20 min peak by 40 min after application of the latter stimuli. CRF content increased to a second peak 80 min after laparotomy with intes inal traction or adrenalectomy. This rise in CRF must represent increased formation of the releasing factor because ACTH levels were elevated and constant for the preceding 60 min. Aftersham-adrenalectomy or adrenalectomy with corticosterone replacement, CRF content and ACTH arelow at 80 min. Measurement of circulating ACTH levels in conjunction with CRF content after hese stimuli have yielded information to assign mechanisms of altered synthesis and secretionto explain the observed changes in CRF content. Corticosterone damps the adrenocortical system response to the stimuli of shamadrenalectomy or adrenalectomy with corticosteron replacement by two mechanisms. Firstly, it acts to inhibit CRF secretion probably via rate-sensitive feedback. Secondly, it acts to inhibit the second wave of CRF formation that is observed 80 min after stress is applied, probably via the proportional feedback mechanism. (Endocrinology97:265, 1975)