Patent foramen ovale (PFO) is a condition present in 20–25% of the general population and can rarely be associated with clinical conditions such as stroke, decompression sickness, desaturation, and migraine with aura. Screening for PFO for primary prevention is not recommended. Several trials have been published demonstrating the efficacy of percutaneous PFO closure in patients under 60 years of age with embolic stroke of unknown etiology. Such evidence has not been achieved in other patient groups, such as those with migraine with aura or decompression sickness. There is also a subset of patients, such as pregnant women or patients undergoing laparoscopic non-cardiac surgery, in whom an increased risk of paradoxical embolism requires preoperative stratification. In all cases, it is necessary to characterize the PFO based on the size of the shunt and the anatomy (e.g., the presence of a large tunnel, prominent Eustachian valve, atrial septal aneurysm), all factors that can increase the risk of paradoxical embolism. This review summarizes the current view on diagnostic and therapeutic work-up of PFO in light of the most recent international guidelines.