Migraine has been associated with patent foramen ovale (PFO), and PFO closure has become the most high-profile nonpharmacologic invasive therapy recommended for the prevention of recurrent migraine attacks, as well as for preventing further attacks in cryptogenic stroke. The results of Migraine Intervention with STARFlex Technology (MIST), a controversial but important recent randomized clinical trial (RCT) of PFO closure for migraine, do not support PFO closure for preventing migraine attacks. All patients with migraine, however, do not have a PFO, and the characteristic periodicity and predictability of migraine cannot be explained on the basis of paradoxical embolism through the PFO. Closure of the PFO or atrial septal defect can aggravate migraine suddenly. PFO increases in size with age, but migraine generally subsides with the passage of years. Serendipity does play a role in some medical discoveries, but in the absence of a logically defensible theoretical basis, chance and statistics can both become misleading. With soft end points, RCTs in migraine patients can generate conflicting and irreconcilable data. RCTs cannot supplant or substitute clinical common sense or justify serendipity. Scientific progress mandates that any serendipitous research must ultimately conform to the principles of the basic sciences surrounding the chance discovery. PFO closure for preventing migraine attacks is an unfortunate, but sobering, chapter in the migraine research saga.