Personalized medicine of antiplatelet drugs in cardiovascular patients has led to a significant enthusiasm. Indeed, numerous longitudinal studies showed an association between high platelet reactivity and the recurrence of ischemic events. The first small randomized trials of P2Y12 blockers tailored to each patient's platelet reactivity yielded encouraging reductions of coronary stent thrombosis in high-risk populations. The discovery of genetic variants contributing to the pharmacodynamic effect of clopidogrel has then paved the way toward a personalized antiplatelet therapy based on reliable and stable genetic tests. This enthusiasm was soon tempered by large interventional trials demonstrating that a platelet function testing-based strategy did not improve clinical outcome and that genetic variants discovered up to now only explained a small part of the pharmacodynamic effect of clopidogrel, thus limiting its clinical use. Looking back to the most recent trials, their target populations and the type of clinical setting, it seems that the one-size-fits all policy regarding antiplatelet drugs may be well acceptable for low-risk patients. On the contrary, integration of the clinical setting as well as other risk factors may help to identify subgroups of patients who could derive a benefit from a truly personalized management of antiplatelet therapy.