The 3 main clinical manifestations of acute coronary syndrome (ACS) are unstable angina, non-ST-segment myocardial infarction, and ST-segment myocardial infarction. Together they comprise a major cause of emergency care and hospitalization in the United States. Consequently, all hospital-based physicians should be familiar with current recommendations regarding the diagnosis and management of ACS. Effective inhibition of platelet activation and aggregation is central to the treatment of ACS, and dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is recommended in all patients with ACS. Recently, the American Heart Association and American College of Cardiology Foundation published focused updates to their guidelines for the management of ACS patients. These updates included changes in antiplatelet therapy arising from the introduction of prasugrel and ticagrelor as alternatives to clopidogrel for the P2Y12 inhibitor component of dual antiplatelet therapy. Among the P2Y12 inhibitors recommended for each indication, the guidelines do not advocate any one P2Y12 inhibitor over another, but instead recommend that therapy is individualized based on each patient's demographic and clinical characteristics. This article presents a clinical case study to illustrate the hospital management of ST-segment myocardial infarction and unstable angina/non-ST-segment myocardial infarction with particular reference to the latest changes in antiplatelet therapy guidelines. This article outlines key differences in the indications and recommendations for P2Y12 inhibitors and summarizes clinical data from the pivotal studies of prasugrel and ticagrelor.