Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is standard therapy after percutaneous coronary intervention and in patients with acute coronary syndromes. Switching from clopidogrel to prasugrel may be required in some patients for efficacy and safety. However, there are potential concerns that overlap of these two agents might increase the risk of bleeding. This review summarizes pharmacodynamic and clinical data to guide clinicians on how and when switching from clopidogrel to prasugrel should be conducted. Loading dose prasugrel should be considered in nearly all indications to avoid any possible gap in adequate platelet inhibition during switching, as overlap of these two agents is unlikely to result in bleeding.