Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A(2) (TxA(2)) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient.