This article is principally intended to describe the facts concerning the actions of 3,5-diiodothyronine (T(2)). Until recent years, T(2), because of its very low affinity for thyroid hormone receptors (THR), was considered an inactive metabolite of thyroid hormones (TH) (thyroxine (T(4)) and triiodo-L-thyronine (T(3))). Several observations, however, led to a reconsideration of this idea. Early studies dealing with the biological activities of this iodothyronine revealed its ability to stimulate cellular/mitochondrial respiration by a nuclear-independent pathway. Mitochondria and bioenergetic mechanisms seem to be major targets of T(2), although outside the mitochondria T(2) also has effects on carriers, ion-exchangers, and enzymes. Recent studies suggest that T(2) may also affect the transcription of some genes, but again the underlying mechanisms seem to be different from those actuated by T(3). The accumulated evidence permits the conclusion that the actions of T(2) do not simply mimic those of T(3) but instead are specific actions exerted through mechanisms that are independent of those actuated by T(3) and do not involve THR.