The deiodinases function at a prereceptor level in tissues to modulate the concentrations, and thus the actions, of thyroid hormones. Although much has been learned in the last two decades about the biochemical properties and expression patterns of these enzymes, a complete understanding of their physiologic roles requires study of their actions in the intact animal. To date only a limited number of naturally occurring human or animal models exhibiting excessive or deficient deiodinase activity have been defined. In particular, no human genetic models of deiodinase deficiency have been identified. However, several transgenic animal models involving either loss-of function or gain-of-function of deiodinase activity have been devised and are currently being characterized. This review focuses on the progress being made in using these animal models to define the physiologic functions and significance of this important class of enzymes.