Steroid nuclear hormone receptors regulate physiological homeostasis through repression and activation of gene transcription. In the absence of hormone, DNA-bound steroid receptors recruit corepressor, such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptorcorepressor (N-CoR), which bind to the free ligand binding domain of the thyroid hormone receptor, retinoic acid receptor, and other nuclear receptors. SMRT and N-CoR form a large protein complex with histone deacetylase I (HDAC1) and Sin3A, which deacetylates histones to alter chromatin structure in a manner that inhibits transcription. In addition, SMRT and N-CoR proteins interact with the transcription factor CBF/RBP-Jk to regulate Notch signaling pathways. SMRT contains four domains related to repressor activity (RD1, RD2, SRD1, and SRD2), two receptor interaction domains (RID1 and RID2), and a SANT region that is found in yeast chromatin remodeling factor SWI3. The ubiquitous expression pattern and corepressor activity of SMRT indicates that this protein is important for hormonal control of gene transcription in many tissues.