THE biological importance of the thyroid gland has been recognized for centuries (1). The realization in the late 19th century that cretinism and myxedema result from loss of thyroid function led to the discovery of T₄ (2) and T₃ (3) as the predominant and most potent thyroid hormones, respectively. During the ensuing decades the plasma membrane (4), synapse (5), endoplasmic reticulum (6), and mitochondria (7) have all been considered as potential cellular sites of action of the thyroid hormones. In the 1960s, however, it was noted that many of the physiological actions of T₃ were preceded by nuclear RNA transcription (8, 9), and high-affinity nuclear receptors for T₃ were discovered soon thereafter (10,11). The specificity of the nuclear T₃ receptors (TRs) for thyroid hormone analogs closely parallels the biological potency of the compounds (12, 13), and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T₃ in most cases (14, 15). Thus, although thyroid hormones may have some important nonnuclear actions, the concept that the majority of the actions of T₃ are mediated by nuclear TRs was generally accepted by the mid-1980s (16, 17). The discovery of multiple TR isoforms and the characterization of their structure, regulation, properties, and function are the subjects of this review.