Before menopause, a woman has a relatively low risk for developing cardiovascular disease. After menopause, however, the risk increases nearly twofold and cardiovascular disease remains the number one cause of death among women. Observational trials and studies in animal models of cardiovascular disease suggested that females have reduced injury after myocardial ischemia and reperfusion injury. However, two large clinical trials, the women's health initiative (WHI) and the heart estrogen and progestin replacement study (HERS), found an increase in cardiovascular incidences in women taking hormone replacement therapy. The discrepancy between these data highlights the need for further research on the mechanism of estrogen in the cardiovascular system. Animal studies have demonstrated protective effects by endogenous estrogen (gender differences) and also by the administration of exogenous estrogen. In vivo studies suggest a possible anti-inflammatory mechanism of estrogen. Exogenous estrogen has been shown to have anti-oxidant activities. Pre-treatment with estrogen prior to myocardial ischemia and reperfusion causes a decrease in neutrophil infiltration into the irreversibly injured myocardium, decrease in C-reactive protein expression, and deposition of the membrane attack complex. This review will summarize the protection afforded by estrogen as well as discuss several possible mechanisms of protection for exogenous estrogen administration.