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With a high prevalence in the general population of approximately 25%, and a prevalence in the cryptogenic stroke population approaching 40%, the propensity of a patent foramen ovale (PFO) to precipitate or enable stroke, especially in young, otherwise healthy individuals, has been the subject of much debate. With proof of concept achieved via imaging modalities documenting thrombus-in-transit, and the development of minimally-invasive percutaneous approaches to closure, multiple observational studies and, more recently, several completed randomized controlled trials have sought to answer the question of when and in whom PFO closure should occur. We describe the historical context of PFO closure and review the observational and randomized control trial evidence in this field, culminating in the recent Food and Drug Administration approval of the first dedicated closure device for PFO. Guidelines and consensus statements are discussed, and a novel treatment algorithm is proposed. Future directions in PFO closure will include new devices, further data from completed and upcoming clinical trials, and potential expansion into other disease states associated with PFO.