AbstractCushing's syndrome (CS) results from prolonged exposure to elevated endogenous cortisol. Majority of cases are caused by ACTH, pituitary, or ectopic origin. Primary adrenal hypersecretion is 15–20% caused by adenomas, carcinomas (ACC), and rarely by nodular adrenocortical disease. CS presents with all typical features. Commonly recommended initial testing are urinary free cortisol, late‐night salivary cortisol, and 1‐mg overnight dexamethasone suppression test (DST). Imaging is the key to diagnosis. CS continues to pose diagnostic and therapeutic challenges; life‐long follow‐up is mandatory. J. Surg. Oncol. 2012; 106:565–571. © 2012 Wiley Periodicals, Inc.