Aspirin, a 110-year-old molecule, is a cornerstone in the treatment of atherothrombotic patients. The concept of aspirin "resistance" emerged approximately 15 years ago and is of growing interest. Aspirin resistance, defined as a lack of inhibition of cyclo-oxygenase-1 (COX-1), is a rare phenomenon and its clinical relevance can hardly be studied. On the contrary, residual platelet hyperactivity is more common and affects 20 to 30% of aspirin-treated patients. This latter phenomenon corresponds to sustained platelet reactivity despite a proper inhibition of COX-1 by aspirin. Several meta-analyses suggest that residual platelet hyperactivity could be a risk factor for the recurrence of ischemic events in aspirin-treated patients. Causes of biological non-responsiveness to aspirin are discussed, including the role of compliance, drug-drug interactions, genetic polymorphisms and diabetes mellitus. Ongoing studies are designed to find out the mechanisms of residual platelet hyperactivity, determine its potential clinical relevance and delineate the more appropriate assays in order to identify patients who may benefit of a tailored antiplatelet therapy.