Calcitonin concentrations in serum were measured by radioimmunoassay during calcium infusion in 76 members of 3 kindreds with known familial medullary thyroid carcinoma. Results were positive in 22 individuals. Six (27%) with normal basal values had abnormal elevations with calcium. Thyroid abnormalities (bilateral cancer in 16 and "C-cell hyperplasia" in 1) were confirmed in all patients who had had surgery. The result of the calcitonin assay was the sole indication for surgery in the 57% without palpable lesions. Distribution of the 31 cases in these families is compatible with an autosomal dominant inheritance, with high penetrance evidenced by calcitonin studies. Studies in 26 relatives of 10 patients with apparently sporadic medullary cancer and in 10 patients with pheochromocytomas disclosed 2 new families with the pheochromocytoma-medullary thyroid cancer syndrome. Thyroid and adrenal lesions were bilateral only in those two families, suggesting that families of patients with bilateral pheochromocytomas or medullary thyroid cancers should be studied for these detectable neoplasms.