The critical step in the development of novel approaches to prevent disease is the translation of laboratory concepts to clinically useful interventions. The expanding database for selective estrogen receptor modulators (SERMs) focuses on the complementary studies of tamoxifen (1) for the treatment and prevention of breast cancer and of raloxifene (2) for the treatment and prevention of osteoporosis. Tamoxifen has been studied thoroughly in breast cancer patients for more than 30 years.1-4 Additionally, the pharmacology and toxicology of raloxifene are now being rigorously evaluated because the primary target is the well woman. In part 2, the important clinical observations will be presented and the toxicological issues will be addressed as a basis for the development of new agents. Tamoxifen is the first clinically useful SERM, so a careful reevaluation of its drug actions is essential for the understanding of drug mechanisms and to avoid toxicological problems in the future with a new agent. Also, the widespread use of tamoxifen as a breast cancer treatment has resulted in renewed laboratory efforts to understand drug resistance. Tamoxifen-stimulated tumor growth is a unique mechanism of resistance, so an understanding of the molecular events that switch a drug from being predominantly antiestrogenic to being estrogenic could potentially open the door to a better understanding of the molecular mechanism of SERM action. This aspect of SERM pharmacology will be addressed at the end of the review with a description of new models of drug resistance to SERM action and potential mechanisms of drug resistance.