Primary cortisol resistance is a disorder of generalized target cell resistance to cortisol caused by a functionally abnormal glucocorticoid receptor (GluR) and characterized by hypercortisolism without other manifestations of glucocorticoid excess. Pituitary resistance to cortisol causes increased release of adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to produce cortisol, adrenal androgens, and mineralocorticoids in greater than normal amounts. The hypothalamicpituitary-adrenal axis is intact, but hormone concentrations are high. Since there is peripheral resistance to cortisol, the hypercortisolism does not produce the expected features of glucocorticoid excess. The increased production of non-glucocorticoid adrenal steroids may cause hypertension, hypokalemia, virilization, and sexual precocity, which bring the patient to medical attention. Primary cortisol resistance must be distinguished from Cushing's syndrome and other causes of hypercortisolism. ACTH concentrations are normal to high, the cortisol response to insulin-induced hypoglycemia is normal, there is a diurnal variation of cortisol secretion, and hypercortisolism is often familial. Confirmation of the diagnosis is dependent upon demonstrasting a glucocorticoid receptor abnormality. Qualitative and quantitative abnormalities of the GluR have been reported, suggesting that this disorder is receptor-mediated and that the molecular basis is heterogeneous. In studies of two different kindreds, two different point mutations have been identified in the GluR binding domain. These may be responsible for the cortisol resistance. Affected subjects with clinical evidence of mineralocorticoid and adrenal androgen excess may require therapy. Dexamethasone in carefully titrated doses will suppress ACTH stimulation of the adrenal glands without causing Cushingoid features.