The ectopic ACTH syndrome accounts for a substantial number of patients with naturally occurring Cushing's syndrome. Despite the progress achieved in elucidating the pathophysiology of Cushing's syndrome, clinicians continue to experience diagnostic and therapeutic challenges. This is especially true in those patients presenting with disease mediated by ectopically produced ACTH and CRH. Patients with these disorders may be indistinguishable based on clinical grounds or simple biochemical and radiologic testing from those with Cushing's disease. However, this differentiation is critical because their therapies differ. While clinical researchers continue to develop more effective diagnostic techniques and therapies, further advances in the molecular and cell biology of ACTH and CRH-producing tumors will undoubtedly shed light on the pathogenesis of this perplexing, fascinating and still controversial entity.