Despite aspirin's and clopidogrel's proven benefit in reducing cardiovascular (CV) events, recurrent CV events still occur in patients receiving antiplatelet therapy. Many of these patients are resistant or only partially responsive to the antiplatelet effects of aspirin and clopidogrel, as determined by standard platelet assays. However, current clinical guidelines do not support routine screening for aspirin or clopidogrel resistance, in part because determination of the most appropriate screening test has not been established. This review attempts to (1) describe the phenomena of clinical aspirin and clopidogrel resistance (ie, treatment failure), (2) discuss the complexity of defining and identifying aspirin and clopidogrel resistance, (3) identify factors that may be responsible for aspirin and clopidogrel resistance, (4) outline several standard platelet function assays and their limitations, and (5) describe potential new antiplatelet therapies that may benefit aspirin- or clopidogrel-resistant patients.