Thyroid hormones regulate fundamental genes involved in the metabolism, development and homeostasis of vertebrates. The endogenous hormones, L-3, 5, 3-triiodo-L-thyronine (T3) and L-3, 5, 3, 5-tetraiodo-L-thyronine (T4), are of limited use in pharmacological intervention, mainly due to cardiovascular liabilities. There exist two subtypes of thyroid hormone receptors (TR), α and β, unequally distributed in the body. As TRα is most abundant in the heart and most effects of thyroid hormones on the heart are mediated through TRα, a reasonable strategy is the development of TR agonists that either are tissue selective or that interact selectively with TRβ. The prospects for the treatment of metabolic diseases with such ligands are considerable and this review describes the massive efforts of the academic and industrial communities during the last decade. It is, however, the authors view that the development of selective ligands only is in its infancy, an opinion highlighted by the limited chemical structural variation of TR ligands as well as the present lack of TR ligands for the treatment of metabolic diseases in clinical phases.