Cardiovascular disease is the number one cause of death in postmenopausal women. Postmenopausal estrogen replacement is associated with a lower incidence of cardiovascular disease in women, especially in those with established coronary artery disease. The strength of the apparent effect of estrogen in epidemiologic studies suggests that estrogen plays a fundamental role in the maintenance of vascular health. Animal data suggest that the current practice of adding the low dose progesterone to prevent endometrial hyperplasia may inhibit the beneficial effects of estrogen on coronary arteries. Before committing millions of postmenopausal women to long-term estrogen use for prevention of coronary artery disease, it is mandatory to demonstrate that it does indeed protect against coronary atherosclerosis, to determine the impact of co-treatment with progestin, and to understand the mechanisms through which estrogen may exert it's cardioprotective effects.