P2Y12 receptor antagonists have become cornerstone pharmacological agents in antiplatelet therapy for patients with acute coronary syndrome or undergoing percutaneous coronary intervention. While clopidogrel remains in extensive use in clinical practice, it cannot meet the needs in many clinical conditions because of its pharmacological limitations. In recent years, newly developed P2Y12 antagonists, such as prasugrel and ticagrelor, have proven to be of higher efficacy and less resistance. With the introduction of these new medicines, the current antiplatelet strategy is undergoing a transitional period. Insufficient platelet inhibition (high platelet reactivity) leads to an increased risk of ischemic events whereas exceeding platelet inhibition can lead to an increased risk of bleeding. This review discusses the pharmacological features, benefits, risks and cost-effectiveness of different P2Y12 antagonists in various clinical settings. A balance between these factors will determine the choice of P2Y12 antagonists for personalized antiplatelet therapy. We conclude that it is a promising option to apply the new drugs, due to their superior therapeutic performance versus that of clopidogrel in the long run.