The antiplatelet agent clopidogrel in combination with aspirin has been shown to reduce thrombotic events in patients with acute coronary syndromes and/or who are undergoing percutaneous coronary intervention. However, a large interindividual response variability to clopidogrel has been described. The reported rates of inadequate clopidogrel response vary considerably depending on the definition and methodologies used to measure the inhibition of platelet function. Recently, several (small) studies have demonstrated the clinical relevance of an inadequate response to clopidogrel. Moreover, several factors have been associated with a high interindividual variability in response to clopidogrel. These are: dosing, impaired intestinal absorption, cytochrome P450 3A4 and 3A5 activity, drug-drug interactions, polymorphisms of the receptors involved in the process of arterial thrombosis and hemostasis, and the method of measurement of platelet function. Future research for the evaluation of clopidogrel resistance should be based on the assessment of selective P2Y12 receptor inhibition (e.g., the vasodilator-stimulated phosphoprotein-assay or the measurement of stabilization of platelet aggregates) with quick and simple tests. Only then can we reveal the true prevalence and impact of clopidogrel resistance.