Coronary artery disease is the leading cause of morbidity and mortality in the Western World. The knowledge base about acute myocardial infarction continues to accrue rapidly with information about pathophysiology, epidemiology, reperfusion therapy, as well as adjunctive treatment strategies. There are however areas where substantial more investigation is required. These include among others 1) patient education strategies for earlier recognition of symptoms which would facilitate earlier and more effective therapy, 2) means to maximize myocardial flow rather than just epicardial flow very early on, 3) an approach to improve myocardial salvage with either adjunctive approaches which are pharmacologic or mechanical, 4) secondary prevention after the initial event including the need for testing and treatment with multiple antiplatelet strategies, 5) ways to define and delivery optimal care with patients with acute myocardial infarction, and 6) new approaches to myocardial cell regeneration therapy. Approaches to these issues will define the future of the treatment of acute myocardial infarction. In this issue of the Medical Clinics of North America, Guest Edited by luminaries David Holmes and Mandeep Singh, we explore these areas and define what works, what has not worked, and what may work in the future.