The genes encoding thyroid hormone receptor α and β (TRα and TRβ) encode four thyroid hormone receptors and four variant isoforms with antagonistic properties. Because of this complexity, numerous models of TR mutation have been developed to understand the functions of specific receptors. In total, 13 mutant strains are now available. Phenotype analysis has shown that the two genes serve distinct functions: TRα is crucial for postnatal development and cardiac function, whereas TRβ mainly controls inner ear and retina development, liver metabolism and thyroid hormone levels. These mouse mutant strains also provide us with the unique opportunity to address the respective contribution of each receptor isoform and isotype in vivo and highlight the in vivo importance of the ligand-independent function of the TR gene products.