Migraine is a chronic disease with episodic attacks, which, when frequent or severe, can be associated with poor quality of life, increased health resource utilization, lost productivity, and significant disability. Preventive therapy can therefore have a significant beneficial clinical and economic impact. However, many migraineurs are treated suboptimally. There is increasing evidence that activation and degranulation of meningeal mast cells result in meningeal irritation, vascular dilation, and stimulation of nearby nociceptive nerve endings of the trigeminal nerve, thus potentially contributing to the pathogenesis of migraine headache. The renin angiotensin system and its peptides are well represented in the mammalian central nervous system and can also promote neurogenic inflammation. Interestingly, mast cells are capable of releasing renin and increasing local production of Angiotensin II. We therefore hypothesize that mast cells contribute to migraine headache through activation of the renin angiotensin system. This hypothesis may help explain the association between migraine and cardiovascular disease as well as observations that medications that modulate the renin angiotensin system can reduce migraine-related morbidity in patients with frequently recurring migraine attacks.