Rarely, nonfunctional pituitary adenomas (NFPAs) may gain secretory function, but there have been a few case reports of metamorphosis to CD.4–17 We describe the clinical course of a man with a proven NFPA whose tumor became functional and began to secrete biologically active ACTH that led to severe Cushing syndrome, review published reports of other cases, and discuss the putative mechanisms of tumor transformation. Here, POMC is linked to Cushing syndrome due to macronodular adrenal hyperplasia.