The major physiologic function of type 1 iodothyronine deiodinase (D1) is to produce triiodothyronine (T(3)) for the plasma. D1 activity is regulated by numerous factors, perhaps the most important of which in human pathophysiology is T(3). T(3) induces D1 expression, contributing to the T(3) excess commonly found in hyperthyroidism. Cytokines, nutritional status, sex steroids, and other factors also regulate D1 activity, although different organs often show different responses. Numerous homeostatic mechanisms can counterbalance isolated changes in D1 expression, such as the genetically decreased expression in C3H/He mice. Two relatively commonly used drugs, propylthiouracil and amiodarone, inhibit D1, which can have substantial effects on circulating thyroid hormone levels. Overall, many factors interact in complex ways to establish D1 levels, contributing to the circulating concentrations of thyroxine (T(4)) and T(3).