Platelet activation and aggregation play a major role in the pathogenesis of acute coronary syndromes. While clopidogrel has convincingly been shown to reduce atherothrombotic events in patients with acute coronary syndromes, and following percutaneous coronary interventions (PCI), a significant portion of patients continue to suffer cardiovascular events. A growing body of literature suggests that at least part of this treatment failure can be attributed to resistance to anti-thrombotic treatment in these patients. The purpose of this review is to clarify the current knowledge regarding clopidogrel resistance.