Cardiovascular disease is the leading cause of death among men and women in the U.S. and other developed societies. However, myocardial infarction and stroke are uncommon in women until their sixth decade and beyond. Clinicians have long suspected that the delay of a decade or more in cardiovascular disease expression in women relative to men is due to the protective effects of estrogen prior to menopause. Reports from population based observational studies of the favorable effects of hormone replacement therapy on cardiovascular morbidity and mortality have led to enthusiasm for widespread use of estrogen by postmenopausal women for the prevention of cardiovascular disease. In support of the antiatherogenic potential of estrogen are studies in postmenopausal women showing favorable effects on lipoprotein levels, fibrinolysis, and vascular function. However, a secondary prevention trial in postmenopausal women with coronary artery disease showed no cardiovascular benefit of hormone replacement therapy. Ongoing clinical trials and options to conventional hormone replacement therapy for cardiovascular protection will be discussed in this review.