Aspirin is an irreversible inhibitor of platelet prostaglandin synthase activity, and is the most widely prescribed drug for the secondary prevention of cardiovascular disease. In recent years, clinical and laboratory evidence has shown significant individual variability in the response to aspirin and its link to clinical outcome. The term 'aspirin resistance' has been introduced to describe situations when clinical or ex-vivo effects of aspirin are less than expected. The accumulating evidence of increased risk of major adverse clinical events (MACE) associated with 'aspirin resistance' in the settings of acute coronary syndrome (ACS), stroke, and peripheral arterial disease has stimulated the search for ways of overcoming aspirin resistance. Existence of the link between high on-treatment platelet reactivity and atherothrombotic events suggests the common mechanisms for atherosclerosis progression and thrombotic complications with the platelets, being a key cellular interface between coagulation and inflammation. This review article provides a contemporary view on 'aspirin resistance' and discusses its definition, clinical importance, and possible mechanisms in light of recent data on the role of platelets in atherothrombosis.