Objective: To consider why women have less heart disease than men and to review the relation of heart disease risk factors, menopause, and estrogen to the risk for heart disease in women. Design: A review of illustrative publications. Results: Women have less heart disease than men at any given level of every major risk factor, with the possible exception of diabetes, even when the relative risk associated with that risk factor is similar for both sexes. Endogenous estrogen is a plausible explanatory variable, but no studies have shown that it is protective. Estrogen treatment after the menopause appears to reduce women's risk for heart disease, but no clinical trials have been reported that prove the benefit of this or any other intervention, except blood pressure control, in women. Conclusions: Prevention programs can safely recommend nonpharmacologic interventions that reflect the evolutionary norm, such as better diet, more exercise, and not smoking. Pharmacologic interventions to prevent disease require clinical trials.