Platelet activation and aggregation play a major role in the pathogenesis of acute coronary syndrome (ACS) and thrombotic complications following percutaneous coronary interventions (PCI). Antiplatelet therapy with aspirin (ASA) and/or clopidogrel remains one of the most effective therapies for the treatment of ACS and prevention of thrombotic complications following PCI. Nevertheless, not all patients achieve the desired laboratory and/or clinical effect following antiplatelet therapy. These patients have been termed "aspirin resistant" or "clopidogrel resistant". In recent years, several studies regarding clopidogrel resistance have been conducted, and a number of pharmacological therapies, together with new treatments, have been suggested. This review aims to provide an overview of the epidemiology, prevalence, clinical significance and potential solutions regarding clopidogrel resistance.