Medullary thyroid carcinomas (MTCs) are currently defined as malignant tumors with evidence of C-cell differentiation. They comprise 5%-10% of all thyroid malignancies and occur sporadically (75%) or as a manifestation of the type 2 multiple endocrine neoplasia syndromes (25%). Results of calcitonin screening in patients with nodules thyroid disease have revealed a mean prevalence of tumors of 0.61% (range, 0.24% to 2.85%), most of which represent microscopic or incidental MTCs measuring less than 1 cm. While heritable and sporadic tumors contain amyloid and have a lobular to solid growth pattern and polyhedral-to spindleshaped cells, numerous variants of these tumors also occur. C-cell hyperplasia (CCH) has been regarded as the precursor of heritable MTCs, although recent studies suggest that CCH is a clonal process and should be considered a form of intraepithelial C-cell neoplasia. Activating germline mutations of RET, primarily affecting exons 10 and 11, with less frequent involvement of exons 13, 14, 15, and 16, represent the molecular basis for the development of heritable MTCs. Somatic RET mutations, primarily affecting codon 918, occur in a substantial proportion of sporadic MTCs. Five-year and 10-year survivals for sporadic MTCs are 65% and 50%, respectively, with major risk factors for unfavorable outcome including tumor stage, male sex, and age greater than 60 years. With the development of molecular testing for RET mutations, the prognosis for patients with heritable MTCs is generally excellent.