This focus seminar will take the reader through the history and pivotal trials that have formed the current state-of-the-art management for acute coronary syndromes. The identification of a ruptured plaque with thrombus formation and subsequent occlusion or downstream embolization in the coronary artery was the key to developing new and effective treatment strategies. The traditional wait-and-see approach with prolonged bedrest was replaced in the 1980s by immediate pharmacological reperfusion of the occluded coronary artery and long-term aspirin to prevent reinfarction. Mechanical reperfusion with percutaneous coronary intervention with stenting and more intense platelet inhibition with P2Y₁₂ inhibitors further improved outcomes from early 2000s. Adjunctive treatment regimens, including anticoagulants, statins, and neurohormonal inhibition, were found to further reduce mortality and prevent new infarctions. Taken together, the use of new combined pharmacological and interventional treatment strategies has led to a remarkable decrease in 1-year mortality from around 22% in 1995 to around 11% by 2014.