This article reviews gender-specific differences in platelet function and response to aspirin. In contrast with men, women under 65 years of age do not benefit from aspirin therapy in primary prevention of coronary artery disease. Furthermore, the overall mortality after myocardial infarction is higher among women, which cannot simply be explained by age or individual treatment. Platelets play a central role in thrombo-ischemic events leading to myocardial infarction and ischemic stroke. Gender differences in platelet reactivity and "aspirin resistance" have been reported. Several studies using female platelets have shown increased platelet reactivity at baseline and a less effective inhibition of platelet aggregation by aspirin. The mechanisms underlying these differences are still to be elucidated, but influences of female sex hormones may play an important role. As a consequence, inhibition of platelet aggregation in women treated with aspirin may be insufficient, and female patients might benefit from higher maintenance dosages or the use of alternative antiplatelet medications. A potential future role of pharmacogenomics and laboratory monitoring of antiplatelet medications in predicting individual responsiveness is likely. Overall, primary prevention of myocardial infarction in women should be correlated with the individual risk score of the female patient. More studies focused on women are needed to optimize gender-specific therapy and, therefore, to improve clinical outcomes in women with atherosclerosis.