Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist, either clopidogrel or the newer more potent agents prasugrel or ticagrelor, is standard therapy in patients receiving a coronary stent and those with a recent acute coronary syndrome. Switching antiplatelet drug regimen may be required in some patients for efficacy, safety, adherence, and cost considerations. However, there are potential concerns when switching from one agent to another that gaps in effective antiplatelet inhibition could lead to thrombotic events, and overlap of agents might cause excessive platelet inhibition thereby increasing the risk of bleeding. This review considers pharmacodynamic and clinical data to guide clinicians when switching between antiplatelet drugs is considered. Loading dose of the new agent should be considered in nearly all situations to avoid any possible gap in adequate platelet inhibition, as overlap of the 2 agents is unlikely to result in bleeding in excess of that with the more potent drug.