Aspirin, the most widely used antiplatelet agent, irreversibly acetylates the enzyme cyclooxygenase 1 (COX-1), thereby inhibiting platelet thromboxane synthesis and subsequent platelet aggregation. Although aspirin has been demonstrated to reduce the odds of serious atherothrombotic events and death in high-risk patients by 25%, subsets of patients fail to respond to therapy and continue to suffer atherothrombotic events. This aspirin treatment failure may be due to sub-optimal bioavailability (e.g. because of non-compliance or under-dosing) or may be a consequence of the as yet poorly understood phenomenon of aspirin resistance. In this review, we summarize the current laboratory methods used to identify aspirin-resistant patients, outline the cellular mechanisms that may contribute to aspirin resistance, and discuss the clinical implications of this important issue.