Differences in genetic makeup or polymorphisms can affect individual drug response. Detecting genetic variation may help predict how a patient will respond to a drug and could be used as a tool to select optimal therapy, tailor dosage regimens, and improve clinical outcomes. The data are replete relative to the therapeutic efficacy of aspirin (ASA) for the prevention of ischemic events. However, there is a paucity of published data on the relationship between polymorphisms and the clinical effects on ASA. Prothrombotic genetic variations that may contribute to ASA resistance, and increased risk of cardiovascular events may involve: (1) a polymorphism on the cyclooxygenase-1 (COX-1) gene affecting Ser529; (2) overexpression of COX-2 mRNA on platelets and endothelial cells; (3) polymorphism PLA1/A2 of the gene encoding glycoprotein IIIa (GPIIIa); and (4) the homozygous 807T (873A) polymorphism allied with increased density of platelet GP Ia/IIa collagen-receptor gene. Because of the possible increased risk of ischemic vascular events, carriers of these genetic polymorphisms may be resistant to the antithrombotic effects of ASA and should be considered for additional or alternative treatment.