OBJECTIVES: The aim of this study is to review the evidence on the use of antithrombotic therapy and risk of device-related thrombosis after left atrial appendage closure. BACKGROUND: Left atrial appendage closure (LAAC) is increasingly performed for stroke prevention in patients with nonvalvular atrial fibrillation, especially those who cannot tolerate or are ineligible for oral anticoagulation. METHODS: After device implantation for LAAC, different antithrombotic regimens with varying duration of therapy are currently used. Such selection depends on patients' risk for bleeding and physicians' choice. RESULTS: Device-related thrombosis remains an Achilles' heel of LAAC, and the etiology remains incompletely understood. Dual-antiplatelet therapy, and direct oral anticoagulation may have similar safety and device-related thrombosis occurrence in real-world LAAC registries compared with warfarin and aspirin. Device imaging surveillance should be routinely performed to assess for device-related thrombosis, which if diagnosed should be treated aggressively, as it is associated with higher thromboembolic risks. CONCLUSIONS: Given the uncertainties and therapeutic dilemma, the authors provide an in-depth discussion of the options and rationale for antithrombotic therapy post-LAAC.