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Hormone replacement therapy (HRT) has been the method of choice for the prevention of postmenopausal osteoporosis since the early 1990s. Although a number of routes of administration are now available, HRT is still predominantly administered orally. In the United States, HRT formulations traditionally comprise conjugated equine estrogens. In Europe, however, HRT preparations tend to be based on 17 beta-estradiol, a natural human estrogen. Furthermore, distinct patterns of HRT use are apparent based on the age of the woman receiving it. Current recommendations are that early postmenopausal women (in their early 50s) receive sequential combined estrogen/progestogen therapy with continued monthly bleeds, while in women who are at least 1 year postmenopausal, continuous combined HRT, which leads to endometrial atrophy and cessation of monthly bleeding, is preferred. Clinical experience to date clearly demonstrates that long-term HRT unequivocally increases bone mass and reduces the risk of fractures in postmenopausal women, with no significant differences between sequential and continuous combined prescribing regimens. Data demonstrating that antiestrogens such as tamoxifen may preserve bone mass have led to the initiation of large-scale trials to determine the potential clinical utility of such agents for the prevention of osteoporosis in postmenopausal women. Nonhormonal therapeutic approaches are now also available, most notably bisphosphonates and vitamin D analogs. At present, however, traditional HRT remains the regimen of choice for the prevention of postmenopausal osteoporosis, given its additional beneficial effects on acute menopausal symptoms, as well as on the cardiovascular system and brain.