Acetylsalicylic acid (aspirin) and clopidogrel are the most widespread antiplatelet drugs used for secondary prevention of atherothrombotic events in patients with cardiovascular disease, including the dual antiplatelet therapy regimen. Considering the fact that the risk of atherothrombosis is directly related to the vital prognosis, the problem of the efficacy of antiplatelet therapy is one of the most relevant in cardiology. The issue of personalization of antiplatelet therapy, which still has minimal implications in real clinical practice, also deserves attention. In this review, we analyzed the recent data on aspirin and clopidogrel resistance. Possible mechanisms of this phenomenon are considered. The problems related to the definition of diagnostic criteria are discussed. The data on the comorbidity and other clinical factors are summarized.