Dual antiplatelet therapy represents an important advance for patients with established cardiovascular disease. Variable platelet response and potential resistance to therapy have emerged with aspirin and clopidogrel. There is no clear and accepted definition of clopidogrel resistance, but patients with lower responses to clopidogrel are at risk for ischemic events, particularly when they undergo percutaneous coronary intervention. Inconsistent nomenclature about this lower response has led to confusion about its potential clinical importance. The concern about nomenclature is less important than answers to key questions such as its mechanisms, how and in whom to measure platelet function, what levels of inhibition are associated with failure of therapy, what levels are adequate for improved clinical outcomes, and in what ways therapy could be altered in patients with lower responses to improve measures of platelet function and clinical outcomes. One option may be to target more aggressive intervention (higher loading and maintenance doses of clopidogrel or alternative agents) to specific patients who are at greater risk and/or least responsive to standard therapies. Clinically useful risk stratification requires an easily performed and reproducible measure of platelet aggregation, as well as standardized definitions of response that correlate with clinical outcomes. Point-of-care assays of platelet function may ultimately improve the ability of clinicians to modify therapy on the basis of response.