Our understanding of thyroid hormone action has been substantially altered by 
recent clinical observations of thyroid signaling defects in syndromes of 
hormone resistance and in a broad range of conditions, including profound mental 
retardation, obesity, metabolic disorders, and a number of cancers. The 
mechanism of thyroid hormone action has been informed by these clinical 
observations as well as by animal models and has influenced the way we view the 
role of local ligand availability; tissue and cell-specific thyroid hormone 
transporters, corepressors, and coactivators; thyroid hormone receptor (TR) 
isoform-specific action; and cross-talk in metabolic regulation and neural 
development. In some cases, our new understanding has already been translated 
into therapeutic strategies, especially for treating hyperlipidemia and obesity, 
and other drugs are in development to treat cardiac disease and cancer and to 
improve cognitive function.