Quantitative structure-activity correlation studies of thyroid hormone analogues have been utilized to examine (1) in vivo rat antigoiter activities; (2) in vitro binding affinities to intact rat hepatic nuclei, solubilized rat hepatic nuclear protein receptors, and the plasma protein thyroxine binding globulin; and (3) correlations between in vivo antigoiter activities and in vitro binding to nuclear receptors. These studies provide a more precise elucidation of the relative importance of the physiochemical factors which influence thyromimetic activities. In particular, they (1) provide the first systematic QSAR examination of drug-receptor interactions and of the dependence of in vivo activity on such interactions; (2) demonstrate the importance of the interactive effects of the 3' and 5' substituents and of the 4'-OH with each other as well as with nuclear receptors in influencing binding affinity; (3) support the hypothesis that binding to nuclear receptors is the first step in initiating the events which lead to subsequent hormonal expression; (4) show that the free energy of binding to nuclear receptors can be factored into the contributing physicochemical properties of the substituents; and (5) suggest factors that need to be considered in designing new analogues.