There has been a long-standing controversy as to whether Cushing's syndrome is primarily a hypothalamic disorder, with the pituitary simply responding to excess of CRH or other factors, or whether the defect lies at the level of the pituitary. Current data suggest that in nearly all cases, the tumor is clonal, implying a genetic defect at the level of the pituitary. The specific abnormalities underlying the development of corticotroph adenomas remain to be determined. It is certainly possible that the historical controversy has created an artificial dichotomy in our thinking about the pathogenesis of Cushing's syndrome and that hypothalamic factors may play a permissive role in the clonal expansion of a mutated pituitary cell. Finally, the finding of polyclonality in hyperplastic corticotroph tissue from a patient with an ectopic CRH-secreting tumor suggests there may be a more direct role for CRH in the pathogenesis of Cushing's syndrome in rare cases.