The current manuscript is an update of the original Practical Guide, published in June 2013[Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51; Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094–106]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients have to learn how to use these drugs effectively and safely in clinical practice. Many unresolved questions on how to optimally use these drugs in specific clinical situations remain. The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group defined what needs to be considered as ‘non-valvular AF’ and listed 15 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 15 topics are (i) practical start-up and follow-up scheme for patients on NOACs; (ii) how to measure the anticoagulant effect of NOACs; (iii) drug–drug interactions and pharmacokinetics of NOACs; (iv) switching between anticoagulant regimens; (v) ensuring adherence of NOAC intake; (vi) how to deal with dosing errors; (vii) patients with chronic kidney disease; (viii) what to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding?; (xi) management of bleeding complications; (x) patients undergoing a planned surgical intervention or ablation; (xi) patients undergoing an urgent surgical intervention; (xii) patients with AF and coronary artery disease; (xiii) cardioversion in a NOAC-treated patient; (xiv) patients presenting with acute stroke while on NOACs; and (xv) NOACs vs. VKAs in AF patients with a malignancy. Additional information and downloads of the text and anticoagulation cards in >16 languages can be found on an European Heart Rhythm Association web site (www.NOACforAF.eu).