The Women's Health Initiative, which reported an increased risk of stroke with hormone therapy (HT), has had a major impact on the use of these drugs. The increased risk was unexpected because experimental animal studies showed estrogen reduced stroke volume and estrogen improves endothelial-dependent blood flow and improves lipid profiles in humans. The mechanisms of risk are uncertain because of the complexity of actions of estrogen in different doses, with or without progesterone, and the presence or absence of atherosclerotic risk factors. Therefore, future research should focus on identifying the mechanism(s) of risk, determining the differential impact of estrogen on stroke compared with heart disease, and identifying women with vasomotor symptoms who may be at risk of stroke with short-term HT use.