Cardiovascular mortality continues to be high and events continue to occur in patients taking antiplatelet medications. Aspirin and clopidogrel have become integral parts of management in patients with coronary artery disease and after percutaneous angioplasty. However, the platelet responses to aspirin and clopidogrel are not uniform. Diminished or lack of response to these agents has been termed aspirin resistance and clopidogrel resistance. These phenomena have tremendous clinical significance as together they may occur in more than 50% of all patients on chronic therapy with aspirin or clopidogrel. Postulated mechanisms of aspirin and clopidogrel resistance include alterations in genetic, pharmacokinetic, and platelet properties. There is a dearth of information in regard to their clinical significance, methods to test them, and strategies to treat them. Further research is necessary in these areas to identify these patients and treat them appropriately.