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Raloxifene is the only selective estrogen receptor modulator approved for long-term treatment in the prevention of osteoporotic fractures and for the reduction of invasive breast cancer risk in postmenopausal women. The demonstrated beneficial effects on bone and mammalian tissue led clinical and molecular research to focus mainly on these organs, giving less attention to all other systemic effects. The aim of this review was to evaluate all described systemic effects of raloxifene, investigating its molecular and tissutal mechanism of action.A literature research was carried out in electronic databases MEDLINE, EMBASE, ScienceDirect, and the Cochrane Library in interval time between 2000 and 2012.Outcomes were considered in relation to positive/adverse effects concerning bone metabolism, lipid metabolism, coagulation pattern, menopausal symptoms, breast cancer onset, and endometrial cancer onset. Raloxifene acts as an estrogen agonist or antagonist depending on the tissue. This feature is related to specific actions on at least 2 distinct estrogen receptors, whose proportions vary according to tissue type.Raloxifene is a drug for the treatment of osteoporosis and for the prevention of estrogen receptor–positive breast cancer because it guarantees a safety profile on the endometrium. Raloxifene is furthermore an effective therapy in women with increased levels of plasma cholesterol.Raloxifene treatment shifts the coagulation pattern toward prothrombosis, and the patients should be exhaustively informed about the risks associated with therapy. Raloxifene does not show to affect memory and cognition. Finally, it is noteworthy that quality-of-life studies demonstrated some favorable effects of raloxifene.Target Audience: Obstetricians and gynecologists, family physiciansLearning Objectives: After completing this CME activity, physicians should be better able to identify the mechanism of action of raloxifene, treat the adverse effects of raloxifene, prescribe raloxifene for patients with osteoporosis, to prevent estrogen receptor–positive breast cancer, as effective therapy in women with osteoporosis and concomitant increased levels of plasma cholesterol, and select the appropriate patients for raloxifene treatment using the patient’s medical history and risk of thromboembolism.