Platelets play a critical role in pathogenesis of atherothrombotic diseases such as acute coronary syndromes and ischemic stroke. Clopidogrel, a thienopyridine derivative is an effective antiplatelet drug mostly used in combination with aspirin or as a single drug in aspirin intolerant patients. However, despite its proven efficacy in various clinical trials, some patients exhibit impaired response to clopidogrel and have activated platelets while on usual clopidogrel treatment. Although definition and mechanism(s) of this therapeutic failure are poorly understood, it is associated with higher morbidity and mortality as in aspirin resistance. Various causes have been implicated in clopidogrel resistance and alternative therapies are recommended. The aim of this review is to evaluate possible mechanisms, its clinical relevance and alternative treatments of this significant issue.