Type 3 iodothyronine deiodinase (D3) is the physiologic inactivator of thyroid hormones, catalyzing the inner ring deiodination of thyroxine (T(4)) to reverse triiodothyronine (rT(3)) and (T(3)) to 3, 3'-diiodothyronine (T(2)), both of which are biologically inactive. Its physiologic role and pathophysiologic effects in humans can be understood in this context. D3 activity in the normal uteroplacental unit regulates the transfer of maternal thyroid hormone to the fetus and, in patients with consumptive hypothyroidism, the rapid destruction of circulating thyroid hormone by tumoral D3 can produce severe hypothyroxinemia. D3 is expressed in multiple fetal structures, but the uterine endometrium and the placenta are the only normal tissues known to express high levels of D3 activity in the mature human. D3 has also been found in vascular anomalies, in human brain tumors, and in some malignant cell lines. These data have led to the categorization of D3 as an oncofetal protein, but recent data indicate that postnatal expression can be reactivated in normal tissues during critical illness and other pathologic conditions.