Nuclear hormone receptors are not only important drug targets, but have also been the focus of decades of active and highly insightful research. Ten years ago, a review on nuclear receptors was entitled “The Second Decade” and a special issue of Molecular Endocrinology in 2005 dealt with the results of these research efforts. The consensus from nuclear receptor research was of course that the signaling pathways mediated by these receptors warrant further research, even though in principle they appeared to represent the most immediate, seemingly simple signaling pathway from hormone (ligand) binding to gene expression changes. In nuclear receptor molecular biology, estrogen receptor research has additional unique facets: since the discovery of ethinyl estradiol by Inhoffen and Hohlweg in the laboratories of Schering AG in the 1930s—and therefore several decades longer than nuclear receptor - searchitself—estrogenreceptorshavebeentargetsofwidelyused,orally administered drugs. Thus, accumulating clinical experience on estrogen action in vivo helps to support the progress in molecular biological research.