Thorough family studies that used the radioimmunoassay procedure for calcitonin (CT) during the past 12 years have provided data on 70 patients from 12 kindreds with hereditary medullary thyroid cancer (hereditary group) and 28 patients with sporadic or nonhereditary medullary thyroid cancer (sporadic group). Serum CT elevations after total thyroidectomy as evidence of residual tumor have been encountered in 21 of 25 patients in the hereditary group with palpable tumors preoperatively (84%) and in 13 of 24 in the sporadic group (54%). However, none of 26 patients with hereditary nonpalpable lesions found by family screening studies have been found to have postoperative CT elevations. Both cervical lymphadenectomy in patients with lymph node involvement at initial operation and reexploration in those with CT elevations after total thyroidectomy have been unsuccessful in the eradication of metastatic disease. These data emphasize the value of thorough family studies that use stimulated CT measurements in the detection of early and curable neoplasms. Involvement of the parathyroid glands or the adrenal medulla that occurred in the hereditary multiple endocrine neoplasia syndromes varied from family to family; it influenced the clinical course and required regular surveillance with calcium and catecholamine studies. Separation of hereditary from sporadic cases has practical value in the identification of family members at risk and also in the provision of prognostic data.