Antiplatelet drug therapy has become one of the cornerstones of treatment for patients with cardiovascular disease. Large clinical trials have shown that antiplatelet medications have important clinical benefits and prevent adverse outcomes in patients with coronary artery disease. Recurrent adverse cardiovascular events still occur in a substantial proportion of patients on standard dual antiplatelet therapy, however, which has been attributed to nonresponsiveness to this treatment. Both pharmacological and pharmacokinetic mechanisms are involved in variability in responsiveness to antiplatelet agents, and include drug bioavailability, medication noncompliance, drug-drug interactions, cytochrome P450 activity, and genetic polymorphisms. Numerous observational studies have consistently shown an association between antiplatelet drug nonresponsiveness and adverse clinical outcomes. However, these studies are limited by varying antiplatelet drug dosing regimens, heterogeneous laboratory assessments for ex vivo platelet function, and wide interindividual variation in platelet responses. Only within the last 2 years have randomized clinical trials indicated that increased dosing with antiplatelet drugs could reduce adverse clinical outcomes. Nonetheless, large clinical trials with standardized laboratory methods and well-defined protocols are needed that will definitively determine the association between antiplatelet drug nonresponsiveness and clinical events, and establish therapeutic strategies to overcome blunted antiplatelet effects.