Estrogen is important in human health and diseases. Estrogen binds to estrogen receptors (ER), alpha and beta which subsequently function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the first SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The strategy for the therapeutic and preventive applications of tamoxifen was initially demonstrated in the laboratory which laid the foundation for its success in the clinic. Unfortunately, use of tamoxifen is associated with de novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to understand the mechanism of SERM action which may further help in designing new and improved SERMs. Clinical studies demonstrate that another SERM, raloxifene, used to treat postmenopausal osteoporosis, is also as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings provide opportunities for SERMs as a new class of drugs which not only can be used for therapeutic and preventive purposes of breast cancers but also for other disease states. The goal is to create new SERMs with a better therapeutic profile and fewer side effects.