Aspirin reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one quarter. The term 'aspirin resistance' has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Various factors such as genetic, nonadherence, variable response to different doses, co-morbid conditions and drug interactions are responsible for aspirin resistance. Many methods, with their limitations, are available to measure the effects on platelets. Despite treatment failures, aspirin remains the single most cost-effective drug for the secondary prevention of atherothrombotic disease. To optimize its clinical effectiveness, clinicians should be aware of the potential causes of aspirin treatment failure, prescribe aspirin in appropriate doses, and encourage patients to take aspirin, stop smoking, and avoid regular use of NSAIDs.