Almost 30 yr of studies have yielded a model for steroid hormone action that, except for the localization of steroid-free receptors, is basically the same for all steroids. At least for glucocorticoid receptors, the rate-determining step in nuclear binding is activation (l-3), in which receptor-steroid complexes acquire an increased affinity for nuclei and DNA. The amount of activated complex is a function of the rate of steroid dissociation from the receptor, which is also the major determinant of steroid affinity (3, 4). Therefore, the affinity of steroid for receptor has been a predictor of glucocorticoid potency (3-6). In addition, receptor protein is usually the limiting factor for the induction of transcription (7, 8). Such analyses have given rise to the tenet that half saturation of the whole cell receptors by steroid should afford half of the maximal amount of activated complexes, of nuclear bound complexes, and of biological response. Thus a left shift in the dose-response curve relative to the dose-binding curve, such that 50% of the maximal biological response is produced by less than 50% receptor occupancy, should never be observed. In fact, a close correlation between the dose-dependent curves for steroid binding and induction of a biological response is regarded as direct evidence for the requirement of receptors in producing a response (9, 10). This doctrine fits nicely with the conclusion that continued steroid occupancy of receptors is required for biological activity (11 , 12). Not surprisingly, data have been reported which are not compatible with the accepted model. The most common abnormalities are left-shifted dose-response curves and variations in percent agonist activity for an antisteroid. The number of such reports have now grown to the point where they can no longer be dismissed. Adjustments to the model appear inevitable. The purpose of this review is to summarize these data and to discuss one recently proposed modification of the current model. Our focus is on glucocorticoid hormones, but results with all steroids are considered.