In patients with cardiovascular diseases, platelet aggregation plays an important role in development of cardiovascular events and hence its inhibition is important in prevention and treatment of these events. Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome and in those who undergo percutaneous coronary intervention. Currently dual antiplatelet therapy with aspirin and clopidogrel is the standard of care in such patients and has been associated with improved cardiovascular outcomes. However, a significant number of patients experience recurrent cardiovascular events despite being on dual antiplatelet therapy. At present there is growing evidence that these events may be associated with poor response to these antiplatelet drugs and has been commonly called as antiplatelet drug resistance. The exact mechanisms leading to antiplatelet drug resistance are not very well understood but are likely multifactorial. Although the precise definition of antiplatelet drug resistance is lacking, but there is sufficient evidence to support that persistence of enhanced platelet reactivity persists despite use of aspirin and clopidogrel and is associated with adverse cardiovascular outcomes. In this paper, we will review the mechanisms, clinical relevance, methods to evaluate, controversies surrounding the definition along with some recent patents and current and future directions for management of antiplatelet drug resistance.