Medullary thyroid carcinoma (MTC) is a distinctive neoplasm which is derived from the calcitonin-producing intrathyroidal C-cell system and which develops commonly in untreated rats of various strains. Thyroid glands of Long-Evans rats ranging in age from 3 months to 3 years showed a spectrum of C-cell proliferative abnormalities. As compared to 3-month-old control rats, thyroids from 9- to 12-month-old animals exhibited mild diffuse C-cell hyperplasia (CCH). Thyroids from animals ranging from 1 to 3 years of age exhibited progressively more severe C-cell abnormalities including severe diffuse CCH, nodular CCH, and/or MTC. In contrast to the normal basal serum calcitonin levels in controls and in animals with mild diffuse CCH, animals with severe diffuse CCH, nodular CCH, or MTC had elevated basal serum calcitonin values. Nodular CCH was characterized by the replacement and enlargement of individual follicles by C-cells. Larger foci of nodular CCH were characterized by similar changes in multiple adjacent follicles or by an irregular expansion of individual follicles. MTC was characterized by penetration of the follicular basal lamina by C-cells with extension into the adjacent thyroid stroma. In addition to the high incidence of thyroidal C-cell abnormalities, diffuse and/or nodular parathyroid hyperplasia was commonly found. There was no evidence of chronic renal failure in these animals, and the serum calcium levels were within normal limits. Although the stimulus for the initial C-cell proliferation remains unknown, the appearance of MTC is preceded by relatively prolonged phases of CCH. These findings are essentially identical with those noted in human familial MTC and indicate that the rat provides a useful model system for studying the regulation of C-cell proliferation during the processes of neoplastic development and progression.