Clopidogrel decreases the morbidity and mortality associated with several cardiovascular diseases. However, clopidogrel is a prodrug that needs to be metabolized to the active thiol metabolite by the cytochrome P450 (CYP) system. This activation is a source of significant interindividual variability in clopidogrel responsiveness. Drug interactions with and genetic variation in CYP3A4, CYP3A5, and CYP2C19 enzymes have been implicated in decreasing active metabolite production. In addition, polymorphisms in the genes encoding P-glycoprotein (an efflux transporter) and purinergic receptor P2Y(12) (the active site for clopidogrel) have been studied for their role in clopidogrel responsiveness. Several large studies have recently assessed the role of genetic variation in clopidogrel responsiveness as characterized by clinical outcomes. In this review, we summarize the genetic causes of clopidogrel nonresponsiveness, with a focus on larger outcomes-based studies. A MEDLINE search of the English-language literature (1990-2008) was conducted to identify studies that examined these relationships; additional citations were obtained from the articles retrieved from the literature search. Polymorphisms in CYP2C19 and, to a lesser extent, the adenosine 5'-triphosphate-binding cassette gene, ABCB1, contribute to variability in clopidogrel responsiveness. Specifically, patients possessing at least one variant CYP2C19 allele (CYP2C19*2, *3) have impaired clopidogrel responsiveness due to decreased formation of the active metabolite. In addition, one study found that considering ABCB1 genotype in addition to CYP2C19 allowed better prediction of clopidogrel nonresponsiveness. However, routine genotyping for CYP2C19 or ABCB1 polymorphisms in order to predict clopidogrel responsiveness cannot be recommended at this time because of logistic and cost considerations.