A patent foramen ovale (PFO) is found with increased frequency in patients with stroke of undetermined origin but the significance and therapeutic implications of this observation remain unclear. Several lines of evidence suggest a role for the PFO in stroke pathophysiology for some cryptogenic stroke patients, such as those whose PFO is accompanied by a prothrombotic state, atrial septal aneurysm, or lower extremity/pelvic DVT. Diagnostic evaluation of the patient with cryptogenic stroke and PFO is directed at identifying these subgroups. Appropriate therapy for primary and secondary stroke prevention in a subject with a PFO remains unclear given current uncertainties as to the pathophysiological significance of PFO. Additional studies are needed, such as those focused on lower extremity veins or the cardiac interatrial septum, to guide therapy in specific stroke subpopulations.