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Thyroid hormone (TH) elicits an extraordinary multiplicity of biochemical, cellular, and physiological responses in the simplest to the most complex organisms. The diverse actions of the biologically active thyroid hormone, L-triiodothyronine (T3), can be divided into two groups: growth and development, and regulation of metabolism. A large number of mechanisms, some mutually contradictory, have been proposed to explain the actions of this hormone. A chronological examination of the mechanisms of action of TH and other hormones reflects the rapid increase in our knowledge of biological regulatory processes. The discovery in the 1980s that the two TH receptors, TRa and TRb, share the same modular structure as other members of the large nuclear receptor multigene family of transcription factors focused attention on transcriptional regulation by TH. TH receptors function together with co-activators and co-repressors in multi-protein complexes, which are organized along with hormonal target genes into the structure of chromatin. Many new facets of TH action are beginning to attract our attention, so that investigators will still be busy attempting to explain the mechanism of its action for decades to come.