The vasculature has been recognized as an important target of estrogen action through rapid non-genomic effects and/or via the classic pathway (genomic effects) involving estrogen receptors (ER-alpha and ER-beta). Multiple mechanisms participate in the regulation of different estrogen-controlled genes, providing a wide spectrum of possibilities for development of drugs, including pure agonists or antagonists or mixed agonists/antagonists, the so-called selective estrogen receptor modulators (SERM). In theory, an ideal SERM should reduce the risks of coronary heart disease (CHD) and preserve bone density, without or with very low incidences of breast and endometrial neoplasms or venous thromboembolism (VTE). The precise mechanism for the protective effects of estrogens and their receptors on cardiovascular diseases is not yet fully established. In this review, we summarize the recent advances in understanding the action of ERs/ligands, the therapeutic implications for CHD, and highlight the recent progress of both clinical and basic studies on the protection issue. Finally, a number of newly developed SERMs and their clinical applications as well as the laboratory investigations are discussed.