Thyroid hormone exerts its actions on gene expression through interactions with its nuclear receptor, the thyroid hormone receptor (TR). TR signaling is complicated by separate soforms that interact with thyroid hormone response elements to regulate gene expression in a positrve and negative fashion. On positive thyroid hormone response elements, the TR interacts with the corepressors, nuclear receptor compressor (NCoR), and silence mediator of retinoic acid and thyroid hormone receptors (SMRT), to mediate ligand-independent repression through the modification of chromatin by histone deacetylation. The presence of ligand causes the release of corepressors and the recruitment of a coactivator complex containing proteins that possess intrinsic histone acetyltransferase activity, which allows for transcriptional activation. The role of these cofactors on genes negatively regulated by the TR is less clear. The identification of TR cofactors has shed light on the pathogenesis of the syndromes of resistance to thyroid hormone where mutations in several distinct domains have identified areas of the TR that are necessary for corepressor release, which is essential for normal TR function. Despite these advances, much is to be learned about the specificity of TR interactions with corepressors and coactivators and the roie of the separate TR isoforms in the diverse effects of thyroid hormone.