A patent foramen ovale (PFO) is a congenital remnant of the fetal circulation that persists in 25% of adults. Once considered a mostly benign congenital heart defect, the presence of PFO-mediated right-to-left shunt has been associated with several clinical conditions, including cryptogenic stroke, migraine with aura, myocardial infarction, peripheral embolism, symptomatic arterial desaturation, exacerbation of obstructive sleep apnea, hypoxemia out of proportion to the extent of lung disease, decompression sickness, altitude illness, and coronary artery spasm. This review paper will discuss the various PFO-associated conditions, relevant observational and prospective randomized trials, as well as preferred methods to make the diagnosis of a PFO.