Dual antiplatelet therapy (DAPT) is a cornerstone in the management of patients with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The use of intensified or prolonged antithrombotic regimens is invariably associated with a reduction in ischemic risk yet an increase in the risk of bleeding complications. The selection of the optimal antiplatelet therapy in each individual patient remains therefore crucial. In recent years, novel approaches alternative to the conventional DAPT and based on the escalation or de-escalation of P2Y12 antagonists have been proposed. These strategies, chosen according to clinical features, genetic factors, and platelet function, have been developed to optimize and individualize the treatment of patients with coronary artery disease and improve their prognosis. In this review, we summarize recent evidence about escalation and de-escalation strategies (guided and unguided), and discuss the utility of genetic and platelet function tests in patients with ACS and/or undergoing PCI.