: Patients experiencing an acute coronary syndrome are exposed to an increased residual risk of recurrent coronary events. Dual antiplatelet therapy (DAPT) is highly effective in preventing atherothrombotic complications in patients with previous myocardial infarction and current guidelines recommend the prescription of DAPT for at least 12 months in all patients experiencing an acute event. However, recent findings demonstrated that long-term DAPT (over 12 months) is related to a better outcome in patients at high risk, suggesting the use of a long-term DAPT to achieve a better clinical outcome. The choice of DAPT duration is still a difficult issue and a personalized approach to the patients is mandatory to manage both the residual ischemic risk and the risk of bleeding events.The aim of this review is to analyze the pharmacological characteristics of available antiplatelet agents and to revise the use of DAPT in clinical practice, focusing on the benefits of a long-term approach.