Antiplatelet therapy with aspirin and a P2Y receptor inhibitor is the cornerstone of treatment of patients with atherothrombotic disease manifestations. Switching between P2Y inhibitors occurs commonly in clinical practice for a variety of reasons, including safety, efficacy, adherence, and economic considerations. There are concerns about the optimal approach for switching because of potential drug interactions, which may lead to ineffective platelet inhibition and thrombotic complications, or potential overdosing due to overlap in drug therapy, which might cause excessive platelet inhibition and increased bleeding. This review provides practical considerations of switching based on pharmacodynamic and clinical data available from the literature.