Estrogens are small molecules of relatively simple structure, endowed however with the ability to trigger a vast array of physiological responses of significant biological complexity. These responses range from the expression of cell type-specific differentiated cellular responses to induction or inhibition of the expression and function of specific gene products, to cell proliferation, to a direct control of the cell cycle’s regulatory machinery, and to modifications of metabolic and endocrine pathways involving multiple cellular effectors. Since the early investigations of the molecular basis of estrogen’s actions, it has become evident that responsive or target cells are endowed with specific ERs — molecular adapters capable of binding with high affinity to these hormones and, thereby, activated to transduce the hormonal signal to multiple cellular components. The first identification and characterization of such molecules in rodent uterus was made possible in the late 1950’s by the availability of tritium-labeled estrogens of sufficiently high specific activity (Jensen 1960; Glascock and Hoekstra 1959). This led to the proposal by Jensen and Colleagues (1968) and Gorski et al. (1968) of the original, and still current, model of estrogens and other steroid hormones’ actions. According to this model, the hormone diffuses through the plasma membrane of all cells, to be retained only by target cells as stable complexes with specific intracellular receptor proteins. Each receptor binds its cognate steroid with high affinity, with equilibrium dissociation constants (Kds) in the nanomolar range, compatible with the physiological concentrations of free hormones. The stable but reversible interaction between steroids and their receptors results in a functional activation of these proteins that appears to involve their release from ternary and quaternary complexes with heat shock and other proteins (recently reviewed by Pratt and Toft 1997). Conformational and posttranslational changes enable them to accumulate in an active form in the nucleus, where they interact with the genome and, thereby, modulate the rate of gene transcription (Yamamoto and Albaerts 1976). The products of the steroid-responsive genes, in turn, are responsible for the phenotypic changes which are the expression of the specific cellular responses to each hormone (Mueller et al. 1961; O’m Alley et al. 1969). According to this model, selectivity of steroid-hormone action in a given cell is essentially ligand- and receptor-based. Therefore, pharmacological parameters, such as potency, agonist/antagonist activities or cell specificity, are dictated by the concentration of a given receptor in each cell type and its relative affinity for a ligand. This in turn affects the stability of the steroid-protein interactions and, thus, the degree and kinetics of receptor activation.