This chapter presents the evidence for S-equol and the prevention of oxidative stress in skin and the cardiovascular system. Reproductive aging and chronologic aging involve biologic processes that can lead to oxidative stress and chronic diseases in both men and women. Asians have a long life expectancy that may be related to their consumption of soy-containing phyto-estrogens. In addition, Asians produce S-equol, a gut bacterial metabolite of soy daidzein that is a potent antioxidant and binds selectively to estrogen receptor β (ERβ). S-equol, through its binding to ERβ in skin, upregulates the expression of key genes and proteins to reduce oxidative stress. In the cardiovascular system, S-equol binds to endothelial GPR30 (GPER), a membrane-associated estrogen receptor, to enhance endothelial cell activity and to give a favorable cardiovascular risk profile. Based on these findings, S-equol represents a natural, selective estrogen receptor modulator for the prevention and treatment of diseases of the aging population.