Medullary thyroid carcinoma (MTC) is an uncommon neoplasm in children that usually is associated with the multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and with familial medullary thyroid carcinoma (FMTC). Recently, germline mutations in the RET proto-oncogene have been found in patients with these syndromes. Thus, with direct DNA testing, kindred members with MEN 2A, MEN 2B, or FMTC can be identified before clinical of biochemical evidence of MTC develops. It has been hypothesized that prophylactic thyroidectomy early in childhood, based on a positive genetic test, produces a better clinical outcome than thyroidectomy at the time MTC is diagnosed either clinically or biochemically. In the present report, the Washington University experience with MTC in children with MEN 2A and 2B is reviewed. Sixteen patients with MEN 2A who had thyroidectomy based on the biochemical diagnosis of MTC are compared with 14 children with MEN 2A who underwent prophylactic thyroidectomy based on direct genetic testing. In addition, the clinical results of 11 patients with MEN 2B treated for MTC are reviewed. After 3 years of follow-up there has been no biochemical or clinical evidence of MTC among the 14 children who had prophylactic thyroidectomy. Among the 16 children with MEN 2A who had thyroidectomy because of elevated basal of stimulated calcitonin levels, four (25%) have persistent of recurrent MTC after a mean follow-up period of 7.6 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, one has died and seven (70%) of the remaining patients have recurrent MTC after a mean follow-up period of 11 years. The authors conclude that a significant number of children with MEN 2A or MEN 2B, who have clinical of biochemical evidence of MTC before thyroidectomy, have persistent or recurrent disease after long-term clinical follow-up. The diagnosis by direct DNA testing in patients with these syndromes allows prophylactic thyroidectomy before the development of extensive local or metastatic MTC.