Acute ST-segment elevation myocardial infarction continues to be associated with substantial mortality rates. Despite much advancement in care, current treatments have also failed to eliminate the significant risk of morbidity, including reinfarction, reocclusion of the infarct-related artery, and thromboembolic stroke. The potential benefit of early thrombolytic therapy in reducing mortality was first established in 1986. Further benefits of conjunctive therapy with aspirin were demonstrated soon thereafter. This review examines the most significant trends in the pharmacologic therapy of ST-segment elevation myocardial infarction since the publication of these early studies: the development of fibrinolytic drugs with improved clot selectivity and improved pharmacokinetic profiles that simplify administration, making ED or even prehospital thrombolysis more practical. More recent data can be interpreted as showing that regimens that are simpler and easier to administer are also clinically superior. This article reviews pharmacologic advances and evaluates the evidence for their use in EDs.