Antiplatelet therapy is a cornerstone of coronary artery disease treatment and prevention. Aspirin and clopidogrel has emerged as the gold standard combination for patients receiving coronary stent and/or suffering from acute coronary syndrome. Despite their efficacy, recurrent events still occur and resistance to antiplatelet drugs might be one of the responsible factors. Aspirin and clopidogrel resistance are emerging entities primarily defined in biological studies by inability of the drug to achieve expected antiplatelet effect based on platelet function tests. Mechanisms of this variability of response remain complex and partially unknown. Moreover, clinical papers linked this biological entity with worse clinical outcomes, and therefore, tailored therapy based on platelet tests has been proposed. Mean while, new antiplatelet drugs will soon change the field while achieving homogeneous degree of platelet inhibition. The present review aims to summarize biological and clinical data about resistance to antiplatelet therapy, and try to estimate how much this might change our prescription in daily clinical practice.