Prompt restoration of blood flow is the primary treatment goal in ST-segment elevation myocardial infarction to optimize clinical outcomes. The ED plays a critical role in rapid triage, diagnosis, and management of ST-elevation myocardial infarction, and in the decision about which of the 2 recommended reperfusion options, that is, pharmacologic and mechanical (catheter-based) strategies, to undertake. Guidelines recommend percutaneous coronary intervention (PCI) if the medical contact-to-balloon time can be kept under 90 minutes, and timely administration of fibrinolytics if greater than 90 minutes. Most US hospitals do not have PCI facilities, which means the decision becomes whether to treat with a fibrinolytic agent, transfer, or both, followed by PCI if needed. Whichever reperfusion approach is used, successful treatment depends on the ED having an integrated and efficient protocol that is followed with haste. Protocols should be regularly reviewed to accommodate changes in clinical practice arising from ongoing clinical trials.