The 17 beta-estradiol (E2) is a sex hormone that is most abundant and most active estrogen in premenopausal women. The importance of E2 in providing cardioprotection and reducing the occurrence of heart disease in women of reproductive age has been well recognized. There are three subtype of estrogen receptors (ERs), including ERα, ERβ and GPR30 have been identified and accumulating evidence reveal their roles on E2-mediated genomic and nongenomic pathway in cardiomyocytes against various cardiac insults. In this review, we focus on the estrogen and ERs mediated signaling pathways in cardiomyocytes that determines cardio-protection against various stresses and further discuss the clinical implication of ERs and phytoestrogens. Further we provide some insights on phytoeostrogens which may play as alternatives in estrogen replacement therapies.