Most patients with major depression have increased 24-hour urinary free cortisol and cortisol nonsuppression after dexamethasone administration, which are cornerstones of a diagnosis of Cushing's syndrome. Similarly, Cushing's syndrome patients often suffer from major psychiatric syndromes, most often depression. These similarities between the two conditions sometimes make it difficult to differentiate them and have led some investigators to suggest they are two points on a spectrum of endocrinologic dysfunction. This article reviews the literature comparing Cushing's syndrome and primary affective disorder and presents two cases that illustrate just how closely these diseases may resemble one another.