Patent foramen ovale (PFO) is a normal fetal communication between the right and left atria that persists after birth. PFO is a common finding that occurs in 20-34% of the population, although its prevalence decreases with age. In most cases, a PFO poses no threat to health. However, some PFOs have the ability to open widely under certain hemodynamic conditions, which enables any bloodborne material, such as thrombi, air, or vasoactive substances, to pass from the venous to the arterial circulation, with the potential to cause a cerebrovascular event. PFO has been linked to several conditions, including cryptogenic stroke, migraine with aura, decompression illness, and systemic arterial embolism. However, the data that support PFO closure in these conditions are mostly from nonrandomized cohort series, and are often contradictory. In this Review, we discuss the existing data on PFO closure, including results of the first randomized, controlled trial comparing device closure of PFO with medical therapy for cryptogenic stroke, and we examine controversies in the literature as well as ongoing studies. We also focus on the anatomy of a PFO and how it impacts on the procedure of PFO closure with a percutaneous device.