Over 1 million coronary stent procedures are performed annually in the U.S., with dual-antiplatelet therapy, which includes the use of both aspirin and clopidogrel, being a cornerstone in the management of these patients after coronary intervention. Now, recent data have surfaced demonstrating altered active metabolite levels of clopidogrel in patients harboring hepatic cytochrome gene variants. These variants, which have been validated through genome-wide association as the dominant explanation for the marked heterogeneity of clopidogrel response, are linked to a significant increase in the risk for bleeding, stent thrombosis, myocardial infarction, and death. With viable alternatives to clopidogrel now available, including higher clopidogrel maintenance and loading doses, prasugrel, and ticagrelor, clinicians can now effectively guide therapy in those with at-risk gene variants by simple genotyping. Such an individualized approach can potentially prevent tens of thousands of adverse cardiovascular events in the over 30% of those with European ancestry and over 40% of those with Asian or African ancestry who harbor these important clopidogrel gain-of-function and loss-of-function alleles.