The adrenocortical response to overnight dexamethasone suppression was determined in normal subjects, in patients with a variety of pituitary diseases other than Cushing's syndrome, and in patients with other disease states. Seventy-nine of 80 normal subjects suppressed 9 am plasma 17-OHCS levels to less than 11.2 μg/100 ml. Of 19 patients with pituitary disease who had one or more normal tests of ACTH reserve, 10 suppressed abnormally in response to dexamethasone. Eleven of 12 patients with deficient ACTH reserve had morning plasma 17-OHCS levels in the normal range after the administration of dexamethasone. However, the low plasma 17-OHCS levels in these patients may have been due to far advanced hormonal deficiency per se. Eight patients of a large group with non-endocrine diseases had impaired suppression of plasma 17-OHCS levels. On the basis of clinical and laboratory findings, there appears to be a spectrum of abnormalities involving ACTH regulation in patients with pituitary disease. These abnormalities range from minimal clinical disease with normal suppression and normal response to stimulation, to early disease associated with impaired suppression and loss of diurnal rhythm but with retention of pituitary responsiveness to stimulation, to the most severe disease with loss of pituitary reserve. The stimulation of ACTH release by any or all of 3 stresses in patients with abnormal suppression implies that stimulation of ACTH release in the human being acts via separate and distinct pathways from inhibition. The abnormality in suppression may be associated with abnormal diurnal rhythm of plasma 17-OHCS.