Several studies found a significant association between patent foramen ovale (PFO), interatrial septal aneurysm, and patients less than 60 years of age presenting with acute stroke and without any identified coexisting mechanism explaining the acute event. Paradoxical embolism from a venous source through a right-to-left shunt is usually incriminated, but the definite proof for paradoxical embolism is often lacking, with screening for deep-venous thrombosis leading to variable estimates. Despite these controversies, the possibility of paradoxical embolism in patients with cryptogenic stroke and PFO is commonly retained as the cause of the neurological deficit. Moreover, there are now definite studies documenting that these patients are at risk of recurrence. The aim of the present paper is to review the literature on the risks of stroke recurrence in patients with atrial septal defects, and to weigh the risks and benefits of the different therapeutic options currently available to prevent stroke recurrence. These options include chronic oral anticoagulant or anti-platelet therapy, and more invasive procedures such as surgical closure or transcatheter closure of the defect. Finally, using the principles of decision analysis, the authors suggest tentative practical therapeutic recommendations that might be helpful to clinicians in daily practice.