Clopidogrel is a prodrug that undergoes extensive enteric clearance and requires two-stage hepatic activation by cytochrome P450 (CYP) enzymes. This metabolic pathway is susceptible to genetic polymorphisms, resulting in a variable platelet inhibitory effect. A growing number of studies have linked poor antiplatelet response to clopidogrel to adverse clinical outcomes, particularly coronary ischemic events and stent thrombosis. This has prompted the development of new ADP receptor antagonists that inhibit platelets more effectively. Two of these agents, prasugrel and ticagrelor, have been investigated in two large randomized clinical trials, and both have shown superiority versus clopidogrel in reducing ischemic endpoints, with an increase in bleeding events, but a favorable final net clinical outcome. Since the publication of the main articles, several sub-analyses have been performed on the same data, and Guideline recommendations have largely endorsed these subgroup findings. Most clinicians have accepted the concept that we might consider approaching the patient differently, deserving a specific agent for each different settings. However, subgroup analyses of randomized trials are often post hoc, underpowered and prone to bias. Weighing efficacy and safety of the most commonly used antiplatelet agents will represent a clinical challenge over the next few years. Furthermore, individuals and organizations involved in formulary decisions will have to face economic constraints, also taking into account the availability of low-cost generic clopidogrel. In the following review, we have performed a critical appraisal of the current literature in order to outline lights and shadows on the most relevant clinical scenarios.