Ectopic POMC syndrome remains one of the most challenging differential diagnoses in endocrinology. Recent progress in the understanding of the tissue specific regulation of POMC gene expression and new insights into the processing of the POMC peptide in nonpituitary tissues has helped elucidate some of the molecular events leading to ectopic expression and secretion of POMC peptides. Corticotropin and other POMC-derived peptides have diverse effects on adrenal steroidogenesis, growth, and extra-adrenal tissues. Differences in POMC gene regulation in the corticotrope versus ectopic POMC-producing tumors provides a scientific framework for the clinical distinction between eutopic and ectopic Cushing's syndrome. In an attempt to revisit recent basic and clinical advances in the diagnosis of ectopic POMC syndrome the authors undertook an extensive literature review of 530 cases in 197 published papers and provided a molecular biologic, demographic and diagnostic update. According to this review, the four most common causes of ectopic POMC syndrome are the small cell carcinoma of the lung (27%), bronchial carcinoids (21%), islet cell tumor of the pancreas (16%), and thymic carcinoids (10%). Although the clinical features of patients with ectopic POMC syndrome are similar to those with Cushing's disease, subgroup analysis reveals a broad spectrum of severity and progression of signs and symptoms of hypercortisolism. The endocrine workup of a patient with suspected ectopic POMC syndrome includes the establishment of pathologic hypercortisolism, diagnosis of corticotropin dependency, and the differential diagnosis of corticotropin-dependent Cushing's syndrome. The use of a variety of baseline endocrine values, dynamic endocrine testing, and invasive procedures leads to the correct diagnosis in the majority of patients with ectopic POMC syndrome. Diagnostic imaging, including conventional radiological techniques and somatostatin receptor scintigraphy, aids in the correct localization and eventual treatment of ectopic POMC production.