There are two biologically active thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃). Most T₃ is produced extrathyroidally, so that alterations in circulating thyroid hormone concentrations may occur as a result of both thyroidal and extrathyroidal abnormalities. Extrathyroidal T₄ conversion to T₃ is decreased in patients with different acute and chronic illnesses. When T₄ conversion to T₃ is impaired and serum T₃ concentrations decline, serum concentrations of biologically inactive 3,3',5-triiodothyronine (reverse T₃) increase. In this review, we present current information on thyroidal and extrathyroidal T₄ and T₃ production in normal subjects and patients with various thyroid diseases and other illnesses, consider the physiologic significance of these changes, and discuss the value and interpretation of various iodothyronine measurements.