The combination of aspirin, heparin, and fibrinolytics was established in the late 1980s and early 1990s as the foundation for pharmacologic reperfusion therapy for ST-elevation myocardial infarction (STEMI). Since that time, many attempts have been made to improve on this regimen with limited success. In the late 1990s, primary percutaneous coronary intervention emerged as an invasive approach for reperfusion that offered superior outcomes to fibrinolytic therapy. However, timely access to experienced cardiac catheterization laboratories remains problematic for the majority of patients with STEMI. Meanwhile, recent advances in adjunctive antiplatelet and anticoagulation therapies have improved outcomes in patients undergoing pharmacologic reperfusion.