The American Heart Association (AHA) and the American College of Cardiology (ACC) have recently updated their joint guidelines for the management of patients with non–ST-elevation acute coronary syndromes (NSTE-ACS, including unstable angina [UA] and non–ST-elevation myocardial infarction [NSTEMI]). These guidelines replace the 2007 guidelines and the focused updates from 2011 and 2012 and now combine UA and NSTEMI into a new classification, NSTE-ACS, and updating the terminology around noninvasive management to ischemia-guided strategy. The latest guidelines include updated recommendations for the use of the oral antiplatelet agents (P2Y₁₂ inhibitors) prasugrel and ticagrelor as part of dual-antiplatelet therapy—the cornerstone of treatment for these patients. This report provides a comprehensive overview of the new and modified recommendations for the management of patients with NSTE-ACS and the evidence supporting them. Also, where appropriate, similarities and differences between the current recommendations of the AHA/ACC and those of the European Society of Cardiology (ESC) are highlighted. For example, the AHA/ACC recommends the P2Y₁₂ inhibitor ticagrelor over clopidogrel in all patients with NSTE-ACS and clopidogrel, prasugrel, or ticagrelor for patients in whom percutaneous coronary intervention is planned, whereas the ESC guidelines specifically recommend individual P2Y₁₂ inhibitors for particular patient subgroups.