We have learned much about molecular mechanisms of nuclear TH action during the past 20 years. In particular, the identification and characterization of TRs, their heterodimeric partners, corepressors, coactivators, and TREs, generation of TR knockout mice, and discovering non-genomic pathways have provided new insight into TH action. It is expected that new information will be obtained from microarray and proteomic studies, structural biology approaches, and in vitro transcriptional systems. Such information should provide an even better understanding of the mechanisms of disease caused by abnormal levels of circulating TH, and could lead to the development agonists and antagonists that may serve as useful therapeutic agents.