Abstract—The optimal therapy for prevention of recurrent stroke or transient ischemic attack in patients with cryptogenic stroke and patent foramen ovale has not been defined. Although numerous observational studies have suggested a strong association between patent foramen ovale and cryptogenic stroke, a causal relationship has not been convincingly established for the majority of affected patients. Treatment choices include medical therapy with antiplatelet agents or vitamin K antagonists, percutaneous device closure, or open surgical repair. Whereas suture closure of an incidental patent foramen ovale is performed routinely during the course of an operation undertaken for another indication, primary surgical repair is rarely advocated in the current era. The choice between medical therapy and percutaneous device closure has been the subject of intense debate over the past several years, albeit one that has not been adequately informed by randomized, prospective clinical trial data to permit an objective comparison of the relative safety and efficacy of these respective approaches. Enrollment in clinical trials has lagged considerably despite frequent calls for participation from the US Food and Drug Administration and major professional societies. Completion and peer review of ongoing trials are critical steps to establish an evidence base from which clinicians can make informed decisions regarding the best therapy for individual patients. The present advisory strongly encourages all clinicians involved in the care of appropriate patients with cryptogenic stroke and patent foramen ovale—cardiologists, neurologists, internists, radiologists, and surgeons—to consider referral for enrollment in these landmark trials to expedite their completion and help resolve the uncertainty regarding optimal care for this condition.