Clopiodgrel therapy is the standard of care in patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention. However, there is a significant amount of interindividual variability in clopidogrel responsiveness. Clopidogrel is a prodrug and requires metabolism via several CYP450 enzymes in order to exert its antiplatelet effects. Interference in these activation steps is the primary cause of clopidogrel nonresponsiveness. This review focuses on genetic polymorphisms in, and drug interactions with, the CYP450 enzymes that are associated with clopidogrel nonresponsiveness. In addition, clinical factors that effect clopidogrel responsiveness are also reviewed. Particular emphasis is placed on those factors that are not only associated with a change in clopidogrel pharmacokinetics or pharmacodynamics, but are also associated with an increased risk of adverse cardiovascular events. Currently, the majority of data assessing clopidogrel nonresponsiveness focus on genetic variation in CYP2C19 and drug interactions with proton pump inhibitors. However, genetic variation in other CYP450 enzymes, other drug interactions and clinical causes have been studied and are also reviewed here. It is important for healthcare practitioners to recognize all of the causes of clopidogrel nonresponsiveness, especially as novel antiplatelet alternatives become available.