The thyroid hormone receptor beta (TR beta) is a nuclear hormone receptor and can function as a ligand inducible transcription factor capable of acting as a co-repressor and/or co-activator for gene expression. Nuclear receptors contain a series of conserved domains or regions. These domains/regions include a variable NH2-domain (A/B region), a conserved DNA-binding domain (DBD or region C), a linker region (region D), a ligand binding domain (LBD or region E), and in some receptors a variable COOH-terminal (region F). The TR DNA binding domain recognizes and interacts with the thyroid hormone response elements (TREs). TR can bind to this half-site, AGGTCA, as a monomer, a homodimer, or a heterodimer with the RXR. The TR/RXR heterodimer is associated with corepressor proteins at the TRE in the absence of ligand. Upon binding of thyroid hormone, TR undergoes a conformational change, releasing corepressor proteins and allowing for the interaction with coactivator proteins that enhance TRE-driven gene transcription. Thyroid hormones affect most mammalian tissues. In excess, these hormones may cause weight loss, tachycardia, atrial arrhythmias, and heart failure. TR isoforms have distinct, nonredundant, and tissue-specific functions. TRα is known as an important regulator of heart function. TR beta appears to be a key regulator of hypothalamus-pituitary-thyroid feedback regulation and plasma cholesterol levels. Mutations in the gene encoding human TR beta have been associated with general resistance to thyroid hormone (GRTH). This disorder is associated with significant behavioral abnormalities.