Antiplatelet treatment is a cornerstone for patients with acute coronary syndromes treated invasively or conservatively to reduce the risk of early and late occurring ischemic complications and to improve survival. Compared to clopidogrel, the novel antiplatelet agents prasugrel and ticagrelor provide faster and more consistent inhibition of platelet aggregation and result in substantially improved clinical outcome in patients with acute coronary syndromes but also an increased bleeding risk. Therefore, balancing the rope between safety and efficacy of treatment is crucial for optimizing outcome. An understanding of the similarities but also differences in pharmacological effect, clinical trial design, and outcome is crucial for understanding which patient populations benefit the most from novel antiplatelet treatments. This review provides recommendations for their optimal use.