Ischemic stroke is one of the leading causes of mortality and the most important determinant of disability in developed countries. Its association with patent foramen ovale is one of the more controversial issues of the literature, also because paradoxical embolism is frequently a diagnosis of suspicion. Up to now, no clinical randomized studies unequivocally demonstrated the causality of this association. Comparing international guidelines there are substantial differences in clinical recommendations among scientific societies, which confirm the uncertainty surrounding this field. Actually, the superiority of transcatheter percutaneous closure over medical therapy alone is not confirmed, partially as a consequence of significant variability in the inclusion criteria, technical approach, peri- and post-procedural therapy among different studies. Moreover, the procedure is very recent and very few studies report prospective data about the safety and effectiveness of patent foramen ovale closure at long-term follow-up. A careful assessment of both clinical characteristics of patients and anatomical features of patent foramen ovale is very helpful to drive a personalized choice for the individual patient. On the basis of the available evidence, this review re-examines the impact of patent foramen ovale in the etiology of cryptogenic cerebrovascular events as well as the advantages and disadvantages of different treatment modalities, waiting for more scientific consensus.