High platelet reactivity (HPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes. Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulate platelets in patients' blood, that characterize the acute phase of acute coronary syndrome are associated with HPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Due to the current possibility not a choice between multiple antiplatelet strategies, the future prospect is to include, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.