Atrial fibrillation (AF) is the most common cardiac arrhythmia and if untreated, significantly increases both the risk of intracardiac thrombus formation and ischemic stroke. In patients with nonvalvular AF (NVAF), the left atrial appendage (LAA) has been estimated to be the source of thrombus development in 91% to 99% of cases. Consequently, oral anticoagulation (OAC) to provide stroke prevention has become the standard of care for most AF patients; however, OACs are associated with a risk of bleeding and their efficacy depends on optimal patient compliance. In terms of alternative approaches to preventing embolic events, surgical LAA excision was attempted as early as in the late 1940s in patients with valvular AF; LAA excision remains a recommendation in surgical guidelines for NVAF patients who need open-heart coronary bypass or valvular replacement/repair surgeries. However, due to its invasive nature surgical LAA intervention has limited clinical application in present cardiology practice. Percutaneous LAA occlusion (LAAO) is increasingly being performed as an alternative to OAC for stroke prevention; this is particularly the case in patients at increased bleeding risk. Substantial progress has been made in percutaneous LAAO therapy since its inception some twenty years ago. Herein we systematically review both the critical literature that led to the development of LAAO, and the increasing clinical evidence supporting the application of this treatment strategy in NVAF. To this end we focus on recently published critical evaluations of United States Food and Drug Administration (US FDA) and Conformité Européenne (Commercial Sale of Licensed Product in the EU) (CE-Mark) approved LAAO devices, summarize the current status of LAAO therapy, and discuss the future perspectives regarding the knowledge and technology gaps in this area by recognizing the potential contributions of many ongoing but likely transformative clinical trials.