In acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), treatment with the P2Y12 inhibitors ticagrelor or prasugrel is recommended over clopidogrel due to a better efficacy, albeit having more bleeding complication. These higher bleeding rates have provoked trials investigating de-escalation from ticagrelor or prasugrel to clopidogrel in the hope of reducing bleeding without increasing thrombotic event rates. In this review, we sought to present an overview of the major trials investigating several different options for de-escalation; unguided, platelet function testing- and genotype-guided. Based on these results, and on other established literature sources, such as guidelines and expert consensus papers, we provide an overview to help decide when and how to de-escalate antiplatelet therapy in ACS patients undergoing PCI.