Patent foramen ovale (PFO) is a common finding in healthy subjects and has not been associated with increased risk of ischemic stroke in population-based cohort studies. Nevertheless, case-control studies have consistently shown an increased prevalence of PFO in cryptogenic stroke, suggesting that PFO might be a cause of stroke. The risk of stroke recurrence in patients with cryptogenic stroke and PFO is low under aspirin therapy but may be substantially higher in patients with an associated atrial septal aneurysm (ASA). The mechanisms of stroke associated with PFO or ASA are uncertain. Paradoxical embolism through the PFO is rarely documented. The optimal treatment for secondary prevention in patients with cryptogenic stroke and PFO is still uncertain and debated. A randomized controlled trial failed to demonstrate the superiority of transcatheter PFO closure over medical therapy. Whether anticoagulation is superior to aspirin should be tested in a randomized controlled trial.