Treatment of patients with cryptogenic stroke and a patent foramen ovale (PFO) has always been a matter of discussion. A clear pathogenic relationship is difficult to demonstrate in most cases, also because of the high prevalence of a PFO in the general population (25-30%). Early randomized trials failed to demonstrate a superiority of PFO transcatheter closure with respect to medical therapy alone but more recent data, coming from new randomized trials, strongly suggest that PFO closure associated with antiplatelet therapy is more effective than antiplatelet therapy alone in preventing recurrent stroke, with no increased risk of major adverse cardiovascular events in the follow-up; only a higher incidence of atrial fibrillation has been reported after PFO closure. PFO closure seems to be more protective only in patients accurately selected on the basis of anamnestic and clinical data together with neurological and cardiological imaging. Pending issues remain such as duration of antiplatelet therapy after PFO closure, the clinical significance of atrial fibrillation before and after PFO closure, and the potential role of old and new oral anticoagulants.