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First, although one-third of strokes are of unclear cause, it is increasingly accepted that many of these cryptogenic strokes arise from a distant embolism rather than in situ cerebrovascular disease, leading to the recent formulation of embolic stroke of undetermined source as a distinct target for investigation. Second, recent clinical trials have indicated that embolic stroke of undetermined source may often stem from subclinical atrial fibrillation, which can be diagnosed with prolonged heart rhythm monitoring. Third, emerging evidence indicates that a thrombogenic atrial substrate can lead to atrial thromboembolism even in the absence of atrial fibrillation. Such an atrial cardiomyopathy may explain many cases of embolic stroke of undetermined source, and oral anticoagulant drugs may prove to reduce stroke risk from atrial cardiomyopathy given its parallels to atrial fibrillation. Non\u2013vitamin K antagonist oral anticoagulant drugs have recently expanded therapeutic options for preventing cardioembolic stroke and are currently being tested for stroke prevention in patients with embolic stroke of undetermined source, including specifically those with atrial cardiomyopathy. Fourth, increasing appreciation of thrombogenic atrial substrate and the common coexistence of cardiac and extracardiac stroke risk factors suggest benefits from global vascular risk factor management in addition to anticoagulation. 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