17beta-estradiol (estradiol), the most abundant endogenous estrogen, affords cardiovascular protection. However, in a given cohort of postmenopausal women, estradiol replacement therapy provides cardiovascular protection in only a subset. The reasons for this variable action can only be understood once the mechanisms by which estradiol induces its cardiovascular protective effects are known. Because most biological effects of estradiol are mediated via estrogen receptors (ERs) and the heart and blood vessels contain both ER-alpha and ER-beta, the prevailing view is that ERs mediate estradiol-induced cardiovascular protection. However, recent findings that estradiol protects against vascular injury in arteries of mice lacking either ER-alpha or ER-beta seriously challenges this concept. Thus other non-ER mechanisms may be operative. Endogenous estradiol is enzymatically converted to several nonestrogenic metabolites, and some of these metabolites induce potent biological effects via ER-independent mechanisms. Therefore, it is conceivable that the cardiovascular protective effects of estradiol are mediated via its endogenous metabolites. On the basis of the evidence cited in this review, the cardiovascular protective effects of estradiol are both ER dependent and independent. The purpose of this article is to review the evidence regarding the cardiovascular protective effects of estradiol metabolites and to discuss the cellular, biochemical, and molecular mechanisms involved.