Migraine-a primary headache-has circadian and circannual rhythms in the onset of attacks. The circadian and circannual rhythms involve the hypothalamus, which is strongly associated with pain processing in migraines. Moreover, the role of melatonin in circadian rhythms has been implied in the pathophysiology of migraines. However, the prophylactic effect of melatonin in migraines is controversial. Calcitonin gene-related peptide (CGRP) has recently attracted attention in the pathophysiology and treatment of migraines. Pituitary adenylate cyclase-activating peptide (PACAP)-a neuropeptide identical to CGRP-is a potential therapeutic target after CGRP. PACAP is involved in the regulation of circadian entrainment to light. This review provides an overview of circadian and circannual rhythms in the hypothalamus and describes the relationship between migraines and the molecular and cellular neurobiology of circadian and circannual rhythms. Furthermore, the potential clinical applications of PACAP are presented.