Human thyroid tumors can be derived either from epithelial follicular cells or from parafollicular C-cells. Follicular cell-derived tumors represent a wide spectrum of lesions, ranging from benign adenomas through differentiated (follicular and papillary) and undifferentiated (anaplastic) carcinomas, thus providing a good model for finding a correlation between specific genetic lesions and histologic phenotype. Follicular adenomas and carcinomas show frequently the presence of mutations in one of the three ras genes. Papillary carcinomas show frequently a specific gene rearrangement which gives rise to the formation of several types of so-called RET/PTC chimeric genes. This lesions occur in almost 50% of papillary cancers and consist in the juxtaposition of the 3' or tyrosine kinase domain of the RET gene (which codes for a receptor protein not normally expressed in follicular thyroid cells) with the 5' domain of ubiquitously expressed genes, which provide the promoter and dimerization functions, necessary for the constitutive activation of RET/PTC proteins. Anaplastic carcinomas are frequently associated with mutations of the p53 tumor suppressor. Finally, point mutations of the RET gene are found in familial endocrine syndromes (FMTC; MEN2A and MEN2B), a common feature of which is the medullary thyroid carcinoma, a malignant tumor derived from parafollicular C-cells.