Antiplatelet agents are the mainstay treatment in the prevention and management of atherothrombotic complications. However, a substantial interpatient variability in response to clopidogrel has been reported. Furthermore, patients with coronary artery disease and lesser platelet inhibition in response to clopidogrel are at increased risk for cardiovascular events. Clopidogrel after absorption requires two-step oxidation by the hepatic cytochrome P450 to generate its active metabolite. Polymorphisms of genes encoding the cytochrome enzymes and P-glycoprotein involved in clopidogrel absorption are regarded as major determinants of the interindividual variability in the clopidogrel-induced platelet inhibition. In our review we discuss the prevalence and clinical significance of various alleles of the genes: CYP2C19 and ABCB1 in the setting of coronary artery disease. Allele CYP2C19*2 is associated with excess of ischaemic events including myocardial infarction and stent thrombosis. On the other hand, CYP2C19*17 allele poses a serious threat of bleeding. Data concerning the prognostic value of genetic variant 3435C→T of ABCB1 remain inconclusive.