During the past 30 years, we have learned a great deal about the molecular details whereby the ovarian hormone elicits the feminizing effects that Knauer described in his experiments over a century ago. The ER plays a pivotal role in this process, and potentially in many other physiological processes. The roles of variant receptors, the details of ER-mediated transactivation and the regulation of ER expression and activation are just a few of the important unresolved issues in this field. These are not trivial problems, and their solutions are likely to require much more investigation. This information will provide important clinical insight into breast cancer, lipid metabolism, bone metabolism, prostatic hyperplasia and other diseases. Armed with this basic knowledge, scientists will be better equipped to design rational therapeutic and preventive strategies to combat these major clinical problems.