Although the medical and technologic revolution in the last 3 decades has improved clinical outcome in patients sustaining acute ST-elevation myocardial infarction (STEMI), residual morbidity and mortality remain major health concerns. The critical roles of temporal delay and optimal sustained patency as modulators of successful reperfusion have been repeatedly demonstrated, and investigation into the ideal interface between pharmacologic and mechanical reperfusion continues. Despite physician awareness and patient education programs, time from symptom onset to treatment in STEMI remains stalled at approximately 3 hours for pharmacologic reperfusion, as documented in major clinical trials. Multifaceted improvements with advanced paramedic training, transmittable 12-lead electrocardiograms, and bolus fibrinolytics facilitate potential prehospital diagnosis and treatment. Thus, as we proceed into the 21st century, it is essential to reexamine strategies for addressing these and other issues relating to the process of delivering optimal care to most patients with STEMI. Especially notable are the opportunities provided through prehospital management with initiation of therapy, triage to appropriate hospitals, or both as major potential avenues to further enhance patient outcomes. We review past research in prehospital therapy for STEMI and practical impediments to implementation to establish a framework for interpretation of future developments.