We report a challenging case of severe ACTH-dependent Cushing’s syndrome without any identifiable pituitary tumor despite adequate MR imaging and two exploratory transsphenoidal surgeries, while preoperative hormonal testing and bilateral inferior petrosal sinus sampling (BIPSS) were highly consistent with a pituitary origin of ACTH secretion. The gene discussed is POMC; the disease is Cushing syndrome due to macronodular adrenal hyperplasia.