SummaryIntroduction:  Despite increasing evidence on the roles of aspirin and clopidogrel in decreasing morbidity and mortality from cardiovascular disease, resistance to therapy remains an emerging clinical entity. The aim of this review was to revisit current knowledge of the mechanisms, laboratory evaluation, clinical impact and management of resistance to aspirin and clopidogrel therapy.Methods:  Potentially relevant studies were identified from an electronic search of MEDLINE and PubMed databases. There were no language or publication year restrictions. References in published articles were also reviewed.Results:  Several definitions for resistance have been set, and various laboratory testing modalities are available. The pathophysiological mechanisms remain poorly understood; yet, several extrinsic, intrinsic and genetic factors are described. The clinical implications of this phenomenon are alarming and warrant concern. Management is currently limited to dosing alteration and introduction of other antiplatelet agents.Conclusion:  Data from ongoing and future studies are awaited to better understand this entity and to highlight the most appropriate treatment strategies.