Abstract Thyroid hormone (TH) is essential throughout life. Its actions are mediated primarily by the thyroid hormone receptor (THR), which is a nuclear receptor. Classically, the THRs act as inducible transcription factors. In the absence of TH, a corepressor complex is recruited to the THR to limit TH-related gene expression. In the presence of TH, the corepressor complex is dismissed and a coactivator complex is recruited to facilitate TH-related gene expression. These coregulators can interact with multiple nuclear receptors and are also key in maintaining normal physiologic function. The nuclear receptor corepressor 1 (NCOR1) and the nuclear receptor corepressor 2 (NCOR2) have been the most extensively studied corepressors of the THR involved in histone deacetylation. The steroid receptor coactivator/p160 (SRC) family and in particular, SRC-1, plays a key role in histone acetylation associated with the THR. The Mediator Complex is also required for pretranscription machinery assembly. This mini-review focuses on how these transcriptional cofactors influence TH-action and signaling, primarily via histone modifications.