The combination of aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACSs) and in those undergoing percutaneous coronary intervention (PCI). At the present time, 3 different oral P2Y12 receptor inhibitors are available on the market; 2 have obtained the indication for ACS (clopidogrel and ticagrelor) and 1 for ACS with planned PCI (prasugrel). An intravenous direct acting P2Y12 inhibitor, cangrelor, has also been recently approved by US and European regulatory agencies for patients undergoing PCI. Although the correct timing and modality of transition from intravenous cangrelor to oral P2Y12 inhibitors is still controversial and needs further evidence, switching between oral P2Y12 receptor inhibitors frequently occurs in clinical practice for several reasons. This practice raises the question of the relative safety of this strategy and of which switching approaches are preferable. In this article, we review the data on switching antiplatelet treatment strategies with P2Y12 receptor inhibitors and discuss practical considerations for switching therapies in patients with ACS undergoing PCI.