Considerable variability exists in how individual patients respond to oral antiplatelet therapy, specifically to aspirin and to P2Y(12)-receptor inhibitors such as clopidogrel. This variability translates to differences in clinical outcomes and might in part be as a result of common variation within genes that are involved in the absorption, metabolic activation, and biological activity of these medications. The field of pharmacogenetics has yielded several genetic loci that predict variation in patient response to antiplatelet therapies. The most robust data indicate an association between loss-of-function alleles of the CYP2C19 gene and adverse outcomes among high-risk patients treated with clopidogrel. However, several fundamental questions surrounding the information gained from genotyping and the efficacy of modifying therapy on the basis of testing remain unanswered. Routine genetic testing for platelet responsiveness cannot, therefore, be recommended for clinical decision-making. Ongoing and future clinical trials might provide evidence to support a change in practice towards pharmacogenetic-based selection of antiplatelet therapy.