Patent foramen ovale (PFO) concerns nearly a quarter of the general population and incidence may reach up to 50% in patients with cryptogenic stroke. Recent randomized clinical trials confirmed that percutaneous closure of PFO-related stroke reduces the risk of embolic event recurrence. PFO also comes into play in other pathogenic conditions, such as migraine, decompression sickness or platypnea–orthodeoxia syndrome, where the heterogeneity of patients is high and evidence for closure is less well-documented. In this review, we describe the current indications for PFO percutaneous closure and the remaining challenges, and try to provide future directions regarding the technique and its indications.