Osteoporosis is a major public health problem and the most obvious preventive strategy, hormone replacement therapy (HRT), has lost favor due to recent findings of the Women's Health Initiative regarding increased risks of breast cancer and cardiovascular disease. Resveratrol, a naturally-occurring compound possessing estrogenic activity, is thought to have considerable potential for therapy of osteoporosis. In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by HRT and decrease the risk of breast cancer in the in vivo and in vitro model. Forkhead proteins were found to be essential for both effects of resveratrol. The bone-protective effect was attributable to induction of BMP-2 through src kinase-dependent estrogen receptor (ER) activation and FOXA1 is required for resveratrol-induced ER-dependent BMP-2 expression. The tumor-suppressive effects of resveratrol were the consequence of Akt inactivation-mediated FOXO3a nuclear accumulation and activation. Resveratrol is therefore anticipated to be highly effective in management of postmenopausal osteoporosis without an increased risk of breast cancer.