Patent foramen ovale (PFO) is a remnant of the normal fetal circulation consisting in a communication between septum primum and septum secundum. Postnatally, the two septa fuse completing separation of the atria. In 25% of normal individuals incomplete fusion leads to the persistence of the flap valve leaving a PFO. In the recent years a variety of clinical conditions has been associated with or attributed to PFO. In particular, PFO has been implicated in the pathogenesis of cryptogenic stroke/transient ischemic attack due to paradoxical embolism and to the pathogenesis of migraine headache. PFO has also been associated with decompression illness in divers and to minor diseases such as platypnea-orthodeoxia syndrome and high-altitude pulmonary edema. Meta-analyses and observational studies indicate that the prevalence of PFO is approximately 3-fold higher in patients with cryptogenic stroke and migraineurs compared controls. Conversely, observational evidences indicate a 2-3-fold increased prevalence of migraine and cerebrovascular events in PFO carriers. Observational studies and meta-analyses suggest that, compared to optimal medical treatment, transcatheter closure of PFO might significantly reduce the recurrence of ischemic cerebrovascular events in patients with previous stroke/transient ischemic attack; however, albeit mechanical closure of PFO is an attractive alternative to medical therapy, randomized trials supporting the efficacy of this approach have not been completed. Furthermore, about 80% of patients undergoing PFO closure for nonmigraine indications reported improvement in their migraine symptoms. However, these studies were predominantly retrospective, nonrandomized and conducted in highly selected populations. The recently published MIST trial, the only randomized study available, failed to demonstrate a significant favorable effect of PFO closure for migraine resolution and/or migraine improvement. At present, as insufficient evidence exists to support transcatheter PFO closure for prevention of cryptogenic stroke recurrence as well as for migraine therapy, and considering that the procedure is not riskless (major complications occurring in 1.5-2% of patients whose PFO was closed), a very prudent and wise approach is imperative in individual patients when this therapeutic strategy is carried out.