Thyroid hormone receptors (TRs) play a central role in mediating the actions of thyroid hormone in development and homeostasis in vertebrate species. The TRs are nuclear receptors that act as ligand-regulated transcription factors. There are two TR genes (TRalpha and TRbeta), each capable of generating different variant products, suggesting a potentially complex array of TR pathways. Targeted mutagenesis in the mouse has indicated that there are specific individual functions for the TR genes in vivo. The deletion of combinations of TRalpha and TRbeta variants has revealed that additional functions are convergently regulated by both TR genes and indicates that control of an extended range of functions is facilitated by a network of specific and common TR pathways. The TR-deficient mouse models have allowed investigation of the TR pathways underlying many functions of thyroid hormone and provide a unique perspective on receptor-mediated mechanisms of biological control.