Aspirin has been shown to reduce the risk of stroke, myocardial infarction, and death in patients with a history of cardiovascular disease or at high risk for cardiovascular disease. However, many individuals suffer a stroke or other cardiovascular event despite aspirin therapy. Data suggest that heritability contributes importantly to the antiplatelet and clinical responses to aspirin. Candidate genes for influencing aspirin response include those involved in platelet aggregation and in modulating cardiovascular disease risk and progression. Although several studies have examined genetic determinants of platelet responsiveness to aspirin, the results are largely inconsistent. Few studies have examined genetic association with clinical outcomes, including reductions in stroke risk, with aspirin. In perhaps the most significant pharmacogenomic study with aspirin to date, a large primary prevention trial showed that the apolipoprotein A genotype was associated with risk of stroke and other cardiovascular events in women and that aspirin eliminated this risk. These data suggest that ultimately, it may be possible to tailor aspirin therapy based on an individual's genotype, at least for primary prevention of stroke and cardiovascular events in women. Data on genetic determinants of response to aspirin in secondary stroke prevention are far less advanced. Future pharmacogenomic studies should focus on elucidating the role of genotyping in choosing appropriate antiplatelet therapy (ie, aspirin alone versus a thienopyridine or combination antiplatelet therapy) for secondary disease prevention.