Epidemiological evidence suggests that soy-based diets containing phytoestrogens (isoflavones) afford protection against cardiovascular diseases (CVDs); however, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which the isoflavones genistein, daidzein, and equol afford protection against oxidative stress remain to be investigated in large scale clinical trials. Isoflavones are transferred across the placenta in both rodents and humans, yet there is limited information on their actions in pregnancy and the developmental origins of disease. Our studies established that feeding a soy isoflavone-rich diet during pregnancy, weaning, and postweaning affords cardiovascular protection in aged male rats. Notably, rats exposed to a soy isoflavone-deficient diet throughout pregnancy and adult life exhibited increased oxidative stress, diminished antioxidant enzyme and eNOS levels, endothelial dysfunction, and elevated blood pressure in vivo. The beneficial effects of refeeding isoflavones to isoflavone-deficient rats include an increased production of nitric oxide and EDHF, an upregulation of antioxidant defense enzymes and lowering of blood pressure in vivo. This review focuses on the role that isoflavones in the fetal circulation may play during fetal development in affording protection against CVD in the offspring via their ability to activate eNOS, EDHF, and redox-sensitive gene expression.