Platelets play a key role in the pathogenesis of acute coronary syndromes and this is why antiplatelet drugs are essential, both in the acute phase and in the long-term follow-up in preventing recurrent myocardial infarction, stroke and cardiovascular death. Aspirin is the most used agent and still remains the first choice drug for lifelong administration in secondary prevention after myocardial infarction. Dual antiplatelet therapy, targeting more than one pathway of platelet activation, has significantly improved the outcome of patients with acute coronary syndromes despite an increased risk of bleeding complications. The aim of this article is to provide an overview of the evidence from randomized clinical trials with a focus on the best association between aspirin and a P2Y12 inhibitor such as clopidogrel, prasugrel or ticagrelor, on the selection of the appropriate agent based on the revascularization strategy and on the optimal duration of such an intensive treatment. We will also provide the latest evidence regarding new antithrombotic agents, such as vorapaxar or low dose rivaroxaban, that could be associated with dual antiplatelet therapy in high risk patients with the aim of further reducing the rate of major ischaemic complications. Finally we will address the issue of patients presenting with atrial fibrillation and a concomitant acute coronary syndrome who frequently need a percutaneous coronary intervention, with a specific focus on the combination therapy of antiplatelet and anticoagulant agents and on the current recommendations of the guidelines.