Deiodinases modify the biological activity of thyroid hormone (TH) molecules, ie, they may activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3), or they may inactivate T3 to 3,3′-diiodo-L-thyronine (T2) or T4 to reverse triiodothyronine (rT3). Although evidence of deiodination of T4 to T3 has been available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP), and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.