New 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 will 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 listed 15 topics of concrete clinical scenarios and formulated as practical answers as possible based on available evidence. The 15 topics are: (1) Practical start-up and follow-up scheme for patients on NOACs; (2) How to measure the anticoagulant effect of NOACs; (3) Drug–drug interactions and pharmacokinetics of NOACs; (4) Switching between anticoagulant regimens; (5) Ensuring compliance of NOAC intake; (6) How to deal with dosing errors; (7) Patients with chronic kidney disease; (8) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding? (9) Management of bleeding complications; (10) Patients undergoing a planned surgical intervention or ablation; (11) Patients undergoing an urgent surgical intervention; (12) Patients with AF and coronary artery disease; (13) Cardioversion in a NOAC-treated patient; (14) Patients presenting with acute stroke while on NOACs; (15) NOACs vs. VKAs in AF patients with a malignancy. Since new information is becoming available at a rapid pace, an EHRA Web site with the latest updated information accompanies this text (www.NOACforAF.eu).