The entry of thyroid hormones into cells has been reported to occur via passive diffusion, facilitated diffusion and receptor-mediated endocytosis. We are studying this process in several tissues: intact skeletal muscle of the rat, continuously cultured rat myocytes and human hepatoma cells. Using the HepG2 human hepatoma cells, we have shown that about 50% of T3 uptake is saturable, and that this saturable uptake is strongly inhibited by phloretin, an inhibitor of dilantin, glucose and non-electrolyte transport. The mechanism of inhibition of T3 and T4 uptake could be due to the biphenol structure of phloretin, causing it to act as a competitive antagonist, or indirectly through its inhibition of glucose transport. Incubation of cells in glucose-free medium also inhibits T3 uptake, but not as completely as phloretin. The rat myoblasts (L6) have also been shown to possess a saturable uptake system from thyroid hormone and work is underway to characterize this process in undifferentiated and differentiated cells. In the intact skeletal muscle, T3 uptake has been shown to increase under the influence of insulin. This increase is prevented by ouabain, an inhibitor of Na-K ATPase, as well as by incubation in a Na-free medium.