Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3-triiodo-Lthyronine (L-T3, 1) and 3,5,3,5-tetraiodo-L-thyronine (L-T4, 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TRα-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5- prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix (helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.