The reduction in mortality from cardiovascular disease has been one of the crowning achievements of medicine over the past century. The evolution in management of acute myocardial infarction (AMI) has played a key role. Yet, the epidemiology of patients with STEMI continues to evolve. The Global Registry of Acute Coronary Events (GRACE) documented that STEMI accounted for ~36% of ACS cases. According to an analysis of a large USA database, the age-adjusted and sex-adjusted incidence of hospitalizations for STEMI significantly decreased from 133 per 100,000 person-years in 1999 to 50 per 100,000 person-years in 2008. Despite advances in both the early management and longer-term treatment of AMI, this condition still represents a leading cause of morbidity and mortality in western countries, making essential understanding its determinants. Early mortality gains noted in all AMI patients may not be sustained over the longer term and reciprocal trends of decreasing mortality after AMI accompanied by an increasing incidence of heart failure have been demonstrated in more recent years. Greater salvage of high-risk MI patients in recent periods may contribute to these trends. Over the past century, insights into the pathophysiology of AMI revolutionized approaches to management through different historical phases. This review provides a historic perspective on the underlying discoveries and pivotal trials that have been the foundation of the key changes of pharmacological and interventional treatment of AMI leading to the dramatic improvement of prognosis during the last tre decades, with special emphasis to the Italian contributions to the field.