Whereas hormonal replacement/menopause therapy (HRT) in post-menopausal women increases the coronary artery risk, epidemiological studies (protection in pre-menopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the atherosclerotic plaque rupture. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits pro-inflammation in vivo, at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, since it stimulates endothelial NO and prostacyclin production, thus promoting beneficial effects of vasorelaxation and platelet aggregation inhibition. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. Estradiol accelerates also endothelial regrowth, thus favoring vascular healing. Finally, most of these effects of E2 are mediated by estrogen receptor alpha, and are independent of estrogen receptor beta. In summary, a better understanding of the mechanisms of estrogen action is required not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses. This should help cardiovascular disease prevention optimization after menopause. These mouse models should help to screen existing and future Selective Estrogen Receptor Modulators (SERMs).