Platelets play a pivotal role in the pathophysiology of ischemic complications of atherosclerotic cardiovascular disease. Aspirin and clopidogrel are oral antiplatelet drugs that have been shown to reduce adverse clinical events across the wide spectrum of patients with atherothrombotic disease. However, recurrent ischemic events still occur in a significant proportion of patients despite treatment with these antiplatelet drugs. The concept of antiplatelet resistance therefore emerges. Although uniform definitions and standardized assays are not yet available, numerous studies have documented the interindividual variability in platelet responsiveness to oral antiplatelet drugs. Evidence is also accumulating to demonstrate that hyporesponsiveness to antiplatelet drugs in the laboratory (ie, resistance) is associated with adverse clinical events in different patient populations. Clinical application of antiplatelet resistance will require proof from prospective randomized trials that modifications of antiplatelet therapy based on tests of antiplatelet responsiveness will improve the outcomes of patients with antiplatelet resistance.