The activation of the RET proto-oncogene contributes to the development of human cancers in two different ways. Somatic rearrangements of RET with a variety of activating genes, which contribute to unscheduled expression and constitutive dimerization of the chimeric RET/PTC oncoproteins in thyroid follicular cells, are frequently found in radiation-induced papillary thyroid carcinomas. Germ-line mutations, mainly point mutations, that lead to constitutive activation of RET tyrosine kinase activity are responsible for the development of the inherited cancer syndrome, multiple endocrine neoplasia type 2. There appears to be a correlation between specific types of RET mutation and clinical phenotypes of the cancers involved. The biological effects and the signaling pathways induced by different forms of RET activation have been investigated in a variety of cultured cells as well as in genetically engineered animal models. The identification of RET mutations in most MEN 2 families (95%) has translated into improved care for MEN 2 patients. However, further investigation of the signaling pathways contributing to tumorigenesis in relevant tissues will eventually help us to develop novel strategies to prevent or to treat human papillary thyroid carcinomas, MEN 2 disease, as well as the sporadic cancers relevant to MEN 2 disease.