The involvement of calcitonin gene-related peptide (CGRP) in migraine pathophysiological mechanisms is shown by the facts that CGRP can induce migraine and that two CGRP antagonists, olcegepant and telcagepant, are effective in the treatment of migraine attacks. Increase of the neuropeptide CGRP during migraine and cluster headache attacks in the extracerebral circulation as measured in the external jugular vein (EJV) has been regarded as an established fact. Then in 2005, a study, using the migraine patients as their own controls, showed; however, no changes of CGRP in EJV. For migraine there is thus some uncertainty as to whether CGRP is increased in all migraine patients and more research is needed. In contrast, there are three 'positive' studies in cluster headache in which both sumatriptan, O(2) and spontaneous resolution normalized CGRP. The source of an increase of CGRP in EJV is most likely a 'nervous vasodilatory drive' in the extracranial vascular bed. It remains an enigma how the observed increase of CGRP in the EJV fits into the mechanisms of migraine and cluster headache.