Antiplatelet therapy represents the cornerstone of treatment for the short- and long-term prevention of atherothrombotic disease processes, in particular in high-risk settings such as in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Currently, dual antiplatelet therapy with aspirin and clopidogrel represents the most commonly used treatment regimen in these settings. However, a considerable number of patients continue to experience adverse outcomes, including both bleeding and recurrent ischemic events. Numerous investigations have demonstrated that this phenomenon may be, in part, attributed to the broad variability in individual response profiles to this standard antiplatelet treatment regimen, as identified by various assays of platelet function testing. In addition, recent studies have demonstrated that genetic polymorphisms may also have an important role in determining levels of platelet inhibition and may be considered as a tool to identify patients at risk of adverse events. This article provides an overview on antiplatelet drug response variability, an update on definitions, including the role of pharmacodynamic testing, underlying mechanisms - with emphasis on recent understandings on pharmacogenetics and drug-drug interactions - and current and future perspectives on individualized antiplatelet therapy.