Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a “back door to the brain”, PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches – opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world’s population.