In 1986, familial medullary thyroid carcinoma (FMTC) was recognized clinically as a distinct entity, clearly distinguished from multiple endocrine neoplasia (MEN), being characterized by the development of MTC in the absence of any additional neoplasms. Ret proto-oncogene was first identified in 1985 using transformation assay. The gene was mapped to the chromosome 10, similar to MEN and FMTC, and was expressed at high levels in MTC. In 1993, ret mutations were identified in patients with MEN2A and FMTC, and many other mutations has been clarified up to today. What is the normal function of RET and how ret mutations lead to tumor formation in MEN and FMTC are focus of intensive studies at present.