Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and confers a fivefold increased risk for stroke. Cardioembolic stroke secondary to AF is a devastating event, but is largely preventable with appropriate oral anticoagulation (OAC). The PROTECT and PREVAIL trials demonstrated that the WATCHMAN left atrial appendage closure (LAAC) device in combination with short-term warfarin therapy is noninferior to long-term warfarin with respect to a composite endpoint of stroke, cardiovascular death, and systemic embolism. Importantly, the WATCHMAN confers a significant reduction in life-threatening bleeding compared to OAC. Although direct-acting oral anticoagulant (DOAC) are superior to warfarin in eligible patients, several important AF populations exist in whom left atrial appendage (LAA) closure may be preferable to DOAC. Populations warranting strong consideration of LAAC include patients with contraindications to DOAC, end-stage renal disease, prior intracranial hemorrhage, recurrent gastrointestinal bleeding, and patients undergoing transcatheter aortic valve replacement or left atrial electrical isolation. Device-related thrombosis is an important complication of LAAC, and DOAC may be preferential to warfarin for prevention and treatment of this complication remains unexplored. Prospective clinical trials comparing DOAC to LAAC in these unique populations are either ongoing or needed.