Given the complex clinical relationship between circadian/sleep regulation and headache, their shared physiological and neuroanatomical basis (see Fig. 1 and reviewed in [9, 28]), the emerging role for the hypothalamus in the regulation of migraine and cluster headache-relevant homeostatic regulation (see [9, 28]) and the emergence of pituitary adenylate cyclase-activating peptide (PACAP) as a key neuropeptide in the regulation of migraine biology [20]. This evidence concerns the gene NPS and migraine disorder.