Recent studies have provided major new insights into the syndromes of inappropriate secretion of thyroid-stimulating hormone (TSH), a heterogeneous group of disorders in which patients show inappropriately elevated levels of serum immunoactive TSH in the presence of elevated free thyroid hormone levels. Certain of these patients appear to have a non-neoplastic disorder associated with variable degrees of pituitary and peripheral resistance to the action of thyroid hormone, whereas others harbor a tumor of pituitary thyrotropic cells. Measurement of free serum alpha subunit has proved valuable in differentiating these disorders, showing normal alpha concentration and alpha-to-TSH ratios in the non-neoplastic and highly elevated values in the neoplastic disorders. All these syndromes appear unrelated to Graves' disease because thyroid-binding and thyroid-stimulating antibodies are usually absent. Some of these patients also have abnormal metabolism of thyroid hormones. Although the pathogenesis of these syndromes remains to be elucidated, increased recognition and study of these patients should provide fundamental insights into the regulation of TSH secretion as well as the action of thyroid hormone.