The antiplatelet drug clopidogrel is a commonly prescribed therapy in patients with acute coronary syndrome. However, its clinical efficacy is hampered by a wide inter-patient response variability, with over 30% of patients treated with this drug experiencing an inadequate antiplatelet response. There are growing evidences that clopidogrel response variability is associated with cytochrome P450 (CYP) enzyme genetic polymorphisms, primarily CYP2C19 which is responsible for the conversion of clopidogrel into its active metabolite. All of the CYP2C19 polymorphism data suggest that carriers of allele *2 or *17 are at greater risk of ischemic or bleeding events, particularly in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Yet, CYP2C19 status explains only 12% of clopidogrel response variability, indicating that genetic variants other than CYP2C19 might be important. Clopidogrel undergoes intestinal efflux via P-glycoprotein, encoded by the ABCB1 gene. The C3435T polymorphism in this gene affects the bioavailability of clopidogrel, however, its effects on clinical outcomes are inconclusive. Similarly, a polymorphism in the gene encoding PON1, a rate-limiting enzyme for clopidogrel bioactivation, also affects the response to clopidogrel. Among nongenetic factors, an adverse drug interaction between proton pump inhibitors and clopidogrel is often reported, but evidence is inconclusive. A genetic test to identify potential responders to clopidogrel might be useful. However, the use of such tests is currently limited because they focus mainly on CYP2C19 loss-of-function alleles, and there is no empirical evidence yet for genotype-guided clopidogrel therapy.