The neuropeptides substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) have been considered as important mediators in migraine and other primary headaches. CGRP and VIP have been found at increased concentrations in jugular venous plasma during attacks of migraine or cluster headache, and CGRP receptor antagonists have recently been shown to be effective in migraine therapy. Substance P and CGRP are produced from a subset of trigeminal afferents, whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges can cause arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments, but only CGRP seems to be relevant in migraine. Animal models have confirmed the important role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and is partly under the control of CGRP, most likely via central mechanisms. CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus seems to facilitate nociceptive transmission via presynaptic mechanisms. The central effect of CGRP is substantiated by suppression of nociceptive c-fos activation and neuronal activity in the spinal trigeminal nucleus following CGRP receptor inhibition. These proposed functions are supported by the localization of CGRP receptor components in the rat cranial dura mater, trigeminal ganglion and spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine; however, central CGRP receptors are likely to be the essential targets in the treatment of migraine using CGRP receptor antagonists.