From observation of recent data linking migraine with right-to-left shunts and by analogy with the etiologies of decompression illness, we postulate that cardiac and pulmonary pathology can have an important effect on the cranial final common pathway that generates attacks of migraine. One possible mechanism is associated with a significant right-to-left shunt, which is usually through a persistent foramen ovale, but is sometime through a pulmonary shunt. This allows a venous agent, possibly 5-hydroxytryptamine, to bypass the lung filter. Migraine can occur when there is no shunt if similar agents are liberated in the left heart beyond the lung filter, possibly by platelet activation. Migraine could also occur if the venous agents are produced in such large amounts that they overwhelm the pulmonary filter or are unaffected by passage through the lungs. In some individuals migraine may be unrelated to blood-borne triggers.