Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y12-receptor inhibitor cangrelor. Dual antiplatelet therapy with aspirin and an oral P2Y12-receptor inhibitor is pivotal for the acute and long-term treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need for strategies directly targeting circulating thrombin or other factors of the coagulation cascade, such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane (vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.