With a steadily increasing prevalence, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and an independent risk factor for stroke caused by thromboembolic events. The left atrial appendage (LAA) is the primary source of thromboemboli in patients with nonvalvular AF who have a stroke. Novel strategies (such as mechanical and nonpharmacological intervention) targeting the LAA in patients with AF for stroke prevention have become a major focus during the past decade. Some devices for percutaneous LAA occlusion are supported by robust clinical data obtained from randomized trials or large registries, and are a valid alternative to pharmacological stroke prevention. However, the incidence of periprocedural complications and the presence of device-related thrombi or residual LAA leaks, whose long-term clinical implications are still unknown, are limiting factors in wider acceptability of these techniques. In this Review, we discuss the available techniques for LAA occlusion in patients with nonvalvular AF at high risk of stroke. We describe the pharmacological and mechanical approaches to LAA occlusion, and provide the current clinical evidence for various strategies. We particularly focus on the current management of the LAA, and discuss the challenges and future implications of the available approaches to LAA occlusion.