Dual antiplatelet therapy--the combination of aspirin and a P2Y12-receptor inhibitor--is the cornerstone of treatment of patients with acute coronary syndromes (ACS) and of those undergoing percutaneous coronary intervention. Prasugrel and ticagrelor have more prompt, potent, and predictable antiplatelet effects than those of clopidogrel, and result in reduced ischaemic outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, clopidogrel is still very commonly used. Switching between oral P2Y12-inhibiting therapies occurs very frequently in clinical practice for a variety of reasons, which raises the question of which switching approaches are preferable. In 2015, cangrelor (an intravenous P2Y12-receptor inhibitor) was approved for clinical use, which adds to the conundrum of how to switch between intravenous and oral therapies. Differences in the pharmacology of P2Y12-receptor inhibitors, such as their binding sites (competitive or noncompetitive), half-life, and speed of onset and offset of action, are important factors that might lead to drug interactions when switching between agents. In this Review, we provide an overview of the literature on switching antiplatelet treatment strategies with P2Y12-receptor inhibitors, and discuss practical considerations for switching therapies in the acute and chronic phases of disease presentation.