Thyroid hormones control growth, development, differentiation and metabolism in vertebrates. Most of the actions of the active thyroid hormone T3 (3,5,3′-triiodo-l-thyronine) are exerted via ligand-activated nuclear T3 receptors. Activation of the secretory product of the thyroid gland, l-thyroxine (3,3′,5,5′-tetraiodo-l-thyronine), or T4, is catalyzed by two enzymes, iodothyronine-5′-deiodinases type I and type II. Inactivation of T4 and T3 occurs via type III iodothyronine-5-deiodinase and to some extent by type I 5′-deiodinase. Complementary DNAs (cDNAs) encoding the substrate-binding selenocysteine-containing subunits of the deiodinases were cloned, though some controversy still exists on the type II 5′-deiodinase subunits. Characterization of tissue-specific expression patterns indicates that these selenium-dependent enzymes exert tight control on local and systemic availability of active T3. Thus, deiodinases are envisaged as guardians to the gate of thyroid hormone action mediated by T3 receptors.