Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F2-isoprostane 8-iso-prostaglandin (PGF2alpha), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.