Mortality rates for acute ST-segment–elevation myocardial infarction (STEMI) have improved dramatically over the past 3 decades: effective reperfusion therapy has been the cornerstone of this improvement, with recent trends showing growth in primary percutaneous coronary intervention (PCI).1 Although mortality rates for routine risk STEMI patients are now ≈5%,2,3 process and procedure challenges remain prevalent. A key area of persistent controversy is optimal anticoagulation during the primary PCI procedure.4–8 Four anticoagulant options are available for primary PCI: heparin, enoxaparin, fondaparinux, and bivalirudin. Clinical practice is heterogeneous in terms of anticoagulant choices, timing, and context of delivery. In a recent study of primary PCI for STEMI performed between 2007 and 2010, US practice reflected this heterogeneity—among over 66 000 primary PCI patients included in the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) registry, 80% received unfractionated heparin, 11% received low–molecular weight heparin, 23% received bivalirudin, and none received fondaparinux.9 Although glycoprotein inhibitors (GPI) are not anticoagulants, it is not possible to discuss primary PCI anticoagulant strategies without mentioning these potent antiplatelet agents—of note, the ACTION registry confirms the relevancy of this drug class, demonstrating that 79% of primary PCI patients in the United States received GPI agents in the first 24 hours of their hospitalization.9 This review will address the issues and controversy of anticoagulation for primary PCI in 4 sections: (1) thrombin generation during primary PCI and the individual characteristics of each anticoagulant, (2) the changing context of primary PCI anticoagulants with respect to other interventional approaches and therapies, (3) an overview of recent controversial trials, and (4) recommended anticoagulation for the clinical practice of primary PCI. ### Pathophysiology Anticoagulation for primary PCI addresses 2 pathophysiologic processes: initial thrombin generation caused by spontaneous coronary plaque rupture and secondary thrombin generation caused by iatrogenic introduction …