Thyroid hormones (L-T3 and L-T4) are important for nearly all human tissues. They have profound effects on metabolic rate and oxygen consumption, but also have unique functions in a variety of organs, including the heart, liver, and pituitary gland, which reflect the specialized nature of these systems. Many of the effects ofthyroid hormone occur at the level of gene expression, and are mediated by nuclear thyroid hormone receptors (TR)'(1). Evidence for the existence andimportance of nuclear TRs with high affinity and specificity for T3 has been recently reviewed by Oppenheimer et al.(2) and, in this journal, by Samuels et al.(3). The purpose of this Per-spective is to provide an up-to-date summaryof new knowl-edge that has directly resulted from the cloning of multiple TRs and related molecules.

Thyroid hormone receptorsare protooncogene products related to steroid and retinoic acid receptors A major breakthrough in our understanding of T3action oc-cuffed when Sap et al.(4) and Weinberger et al.(5) simultaneously discovered that c-erbA, the product of the cellular homologue of the viral oncogene v-erbA (6), has the ability to bind T3 with great affinity and specificity. It had previously been noted that v-erbA was structurally related to the glucocorticoid, estrogen, and progesterone receptors (7-11). Subsequently, receptors for mineralocorticoids (12), androgens (13, 14), vitamin D (15, 16), and retinoic acid (17, 18) were determined to have similar structures. Thus, the TR is a member of a superfamily of intracellularhormone receptors (19, 20). Each receptor interacts with its cognate hormone as well as with the subset of genes responsive to that hormone. DNA binding to target genes is mediated by basic amino acid residues at the tips oftwo highly conserved (40-90%)" zinc finger" structures, formedby the tetrahedral coordination of zinc with four cysteine residues (21). The hormone-binding regions of the receptorsare less well conserved, and are located at the carboxyl termini of the proteins. Multiple thyroid hormone receptors Following the initial isolation of TR cDNAs from chick em-bryo (4) and human placental (5) libraries, it has become clear