Starting with the biological, pharmacological, and clinical significance of the term drug resistance, as exemplified by resistance to chemotherapy, this monograph provides a conceptual framework to analyze the so-called resistance to aspirin and clopidogrel. An extensive and updated review of the literature is provided on platelet physiology, on the mechanism of action of different antiplatelet drugs, and, finally, on the issue of aspirin and clopidogrel resistance. The term resistance for these drugs appears to be uninformative of the mechanisms underlying interindividual variability in response to antiplatelet agents and is potentially misleading. In contrast, several pharmacokinetic and pharmacodynamic factors contribute to a wide interindividual variability of the patient response to several antiplatelet drugs. The major determinants of this interindividual variability are analyzed in this monograph, mainly focusing on aspirin and clopidogrel. With any drug used to prevent atherothrombosis, treatment failure can occur, perhaps not surprisingly, given the multifactorial nature of atherothrombosis. Increased awareness of factors that may interfere with the desired antiplatelet effect, particularly patient's compliance to chronic treatments, avoidable drug interactions, and genetic factors may result in better patient care than may requesting unnecessary tests of platelet function of unproven clinical significance. Recommendations are provided for the practicing physician and clinical investigator on the basis of current clinical and biochemical data.