Migraine is a disabling neurovascular disorder with a complex pathophysiology. Functional imaging and magneto encephalographic studies strongly suggest that Cortical Spreading Depression (CSD) constitutes the biological basis for the neurologic aura that precedes headache in one fourth of migrainers. It is likely that the aura is the generator of the headache since experimentally, CSD triggers the activation of the trigeminovascular system, possibly through matrix metalloproteases activation which is associated with an increase in vascular permeability. These data may have therapeutic implications: strategies to block trigeminal activation or its downstream consequences are central to treat the acute headache whereas strategies to block events lying upstream of trigeminal activation would be crucial in prophylaxis.