Elwood Jensen and Jack Gorski had spent 10 yr providing experimental evidence to support the concept of an intracellular “receptor” protein for steroid hormones. Their combined work had even led to a proposed model by which the interactions of the receptor and the steroid were involved in mediating the cellular effects of the hormone (1). The first of these receptors to be characterized was for the female sex hormone, 17ß-estradiol (E2)(2, 3). Since this time, similar receptors for testosterone, progesterone, glucocorticoids, thyroid hormone, vitamin-D3, and retinoids have been discovered and now form a portion of a large family of nuclear hormone receptors (4). Although significant strides have been made since, Jensen’s introductory statement in a review published more than 25 yr ago is still contemporary with the current research goals toward understanding the growing family of nuclear receptors. This is not to say that little progress has been made, which is quite to the contrary, but rather to state that although advances in technology and molecular biology have allowed for extensive insight, there is still a great deal to be learned as we move into the next century.

Our current understanding of the various roles of the steroid, thyroid, and retinoid hormones in development and normal physiology and the mechanisms by which these actions are mediated is due, in large part, to the generation of a series of reagents and tools over the past 40 yr. The first of these was the synthesis and use of tritium-labeled E2 with high specific activity, allowing for the first reports of the detection and simple characterization of an estrogen-binding component, or “estrophilin”(1, 3, 5). This protein exhibited a binding affinity for estradiol that was several fold higher compared with the other gonadal steroids and was found only in tissues previously shown to respond to estradiol in terms of growth and increased RNA synthesis (1, 3). These studies described the uptake and concentration of radiolabeled estradiol by a specific protein unique to the cells of the uterus, vagina, and pituitary and thereby disputed the current thought that estrogen action required enzymatic metabolism of the hormone (2, 3, 6). Thus, the concept of a hormone receptor protein in target tissues was initiated. Autoradiographic studies with radiolabeled ligand further demonstrated the strong association of estradiol with the nuclei of cells lining the rat uterus within 4 h after injection (7). These studies were significantly advanced by pharmacological approaches with early nonsteroidal estrogen antagonists, the first being the triphenylethylene, MER-25 (2),