Estrogens and selective estrogen receptor modulators (SERMs) have potent skeletal effects that inhibit bone loss and reduce fracture risk. These agents were selected for prevention and treatment of bone loss based on an understanding of the normal menstrual cycle and elucidation of the pathophysiology of postmenopausal bone loss. Full-strength hormone or estrogen therapy appears to have a stronger effect on bone mineral density than SERMs, and more potently reduce fracture risk. Clinical prescriptions for hormone and estrogen therapy decreased significantly after the Women’s Health Initiative Hormone and Estrogen-Alone clinical trials were published in 2002 and 2004, respectively. Hormone and estrogen use have rebounded somewhat over the last decade with the availability of low-dose and transdermal preparations. SERMs have less potent effect than estrogen on increasing bone mineral density (BMD) or reducing fracture risk due largely to their partially antagonistic effects on the estrogen receptor. SERMs have advantages over estrogen in that they minimize the risk of some adverse effects related to estrogen, and have opposite effects than estrogen in other settings. Individual SERMs have unique tissue-specific activities that require documentation in clinical trials, as the clinical profiles of SERMs are moderately variable. The future of SERMs appears to be rich with possibilities, but successful clinical application has been slowed by their variable tissue-specific effects.