Effective stroke prevention with oral anticoagulation (OAC) is the cornerstone of the management of patients with atrial fibrillation. The use of OAC reduces the risk of stroke and death. For most patients with atrial fibrillation without moderate or severe mitral valve stenosis or prosthetic mechanical heart valves, treatment options include vitamin K antagonists, such as warfarin, and non-vitamin K antagonist oral anticoagulants (NOACs). Although most guidelines generally recommend NOACs as the first-line OAC, caution is required in some groups of patients with atrial fibrillation at high risk of stroke and bleeding who have been under-represented or not studied in the randomized clinical trials on NOACs for stroke prevention. In addition to OAC, non-pharmacological, percutaneous therapies, including left atrial appendage occlusion, for stroke prevention have emerged, sometimes used in combination with catheter ablation for the treatment of the atrial fibrillation. High-risk groups of patients with atrial fibrillation include patients with end-stage renal failure (including those receiving dialysis), extremely old patients (such as those aged >80 years with multiple risk factors for bleeding), patients with dementia or those living in a long-term care home, patients with previous intracranial bleeding or recent acute bleeding (such as gastrointestinal bleeding), patients with acute ischaemic stroke and patients with an intracardiac thrombus. This Review provides an overview of stroke prevention strategies, including left atrial appendage occlusion, in patients with atrial fibrillation at high risk of stroke and bleeding.