The thyroid hormone receptors (TRs) are transcription factors that mediate the pleiotropic activities of the thyroid hormone, T3. Four T3-binding isoforms, TRalpha1, TRbeta1, TRbeta2, and TRbeta3, are encoded by two genes, THRA and THRB. Mutations and altered expression of TRs have been reported in human cancers. A targeted germ-line mutation of the Thrbeta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma (TRbeta(PV/PV) mouse). The TRbetaPV mutant has lost T3-binding activity and displays potent dominant negative activity. The striking phenotype of thyroid cancer exhibited by TRbeta(PV/PV) mice has recently led to the discovery of novel non-genomic actions of TRbetaPV that contribute to thyroid carcinogenesis. These actions involve direct physical interaction of TRbetaPV with cellular proteins, namely the regulatory subunit of the phosphatidylinositol 3-kinase (p85alpha), the pituitary tumor transforming gene (PTTG) and beta-catenin, that are critically involved in cell proliferation, motility, migration, and metastasis. Thus, a TRbeta mutant (TRbetaPV), via a novel mode of non-genomic action, acts as an oncogene in thyroid carcinogenesis.