The major developmental targets for thyroid hormone are the brain, small intestine, and bone. Clear defects in gene regulation and tissue function as a consequence of TR gene inactivation can additionally be shown in the pituitary, hypothalamus, heart, and liver. TR gene knockout models show a clear distinction between thyroid hormone requirements for development and those that are required for functions in the adult animal. T3-mediated gene repression appears especially important in a number of tissues including brain, pituitary, and the heart. Preliminary evaluation of the combined TR knockout models suggests that hypothyroidism is associated with more significant abnormalities than receptor deficiency, indicating that the repressive action of the unliganded receptor may have physiological relevance. These various animal models should be very useful to design and test thyroid hormone analogues to selectively stimulate desired thyroid hormone actions.