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The recruitment and activation of blood platelets initiate ischemic events in patients with coronary artery diseases (myocardial infarction). Moreover, platelet activation and aggregation are key events triggering early and late thrombotic complications (stent thromboses) in patients successfully treated with coronary stent implantation. Hence, the inhibition of the thromboxane A2 synthesis by aspirin and the ADP-receptor pathway by clopidogrel have drastically reduced the risk of ischemic complications following coronary stenting. However, clopidogrel has several inherent limitations, including the high incidence of non- or low-responders and the increased risk of bleeding due to the prolonged persistence of its anti-platelet effect. The latter is of particular concern in patients who require non-deferrable surgery. In recent years, novel anti-platelet substances have been clinically evaluated and are now approved for use in patients. These substances offer several potential advantages over the previous strategies and could pave the way for more individualized anti-platelet regimens. In this review, we give an overview on the available clinical data evaluating the benefits of these novel anti-platelet substances.