The biological actions of estrogen analogs have frequently confounded prevailing views regarding the mechanism of estrogen action. Agents originally intended as antifertility drugs are now used clinically to promote ovulation. The early work with antiestrogens as antifertility agents lead to the realization that triphenylethylene antiestrogens suppressed the growth of breast tumors. The subsequent ubiquitous clinical use of tamoxifen for adjuvant breast cancer therapy is a direct result of this research. Basic studies using tamoxifen and related antiestrogens revealed the previously unsuspected tissue selective actions of these compounds. This peculiar property is being taken advantage of to gain new insight into the molecular mechanisms of estrogen action. This property also forms the basis for an exciting new approach to hormone replacement therapy to prevent postmenopausal osteoporosis and cardiovascular disease. The laboratory rat played an integral and essential part in each of these developments. The success of the ovariectomized rat model in predicting the tissue selective effects of tamoxifen in women greatly increases confidence that this animal model will be useful in development of a new generation of estrogen analogs designed specifically for postmenopausal hormone replacement.