Our research on thyroid hormone action is focused on the development of thyroid hormone receptor (TR) isoform-selective ligands. There are two genes that encode two different TR's (TRa and TRb), and these genes are further processed at the mRNA level giving rise to an ensemble of four TR isoforms (TRa1, TRa2, TRb1, TRb2) that are expressed at different ratios in different tissues. The phenotypes of targeted gene knock-out mice indicate that these isoforms mediate specific processes in thyroid hormone regulation, although thyroid hormone shows no selectivity for the different isoforms. We have developed a thyroid hormone analog, called GC-1, that is selective for the TRb isoforms and is proving to be a valuable pharmacological probe for addressing the question of the specific roles of the TR isoforms. We have also recently used the GC-1 structural core to synthesize a thyroid hormone antagonist that blocks thyroid hormone action in vivo. This is the first example of a thyroid hormone antagonist, and this will also be an important probe to study thyroid hormone action. Our long term goal is to develop a set of selective thyroid hormone analogs that can activate or inhibit all of the different TR isoforms. These tools will allow us to fully understand the actions of thyroid hormone and will serve as prototypes for selective therapeutics for the treatment of a large number of diseases that intersect with thyroid hormone signaling pathways.