Over the last 40 years, our understanding of the pathogenesis of myocardial infarction has evolved and allowed new treatment strategies that have greatly improved survival. Over the years, there has been a radical shift in therapy from passive healing of the infarction through weeks of bed rest to early discharge usually within 2 to 3 days as a result of immediate reperfusion strategies and other guideline-directed medical therapies. Nevertheless, challenges remain. Patients who develop cardiogenic shock still face a high 30-day mortality of at least 40%. Perhaps even more important is how do we identify and prevent patients from developing myocardial infarction in the first place? This article discusses these milestones of therapy and considers important issues for progress in the future.