Migraine attacks are triggered by a variety of conditions including endogenous and exogenous factors. Evidence suggests that activation and sensitization of primary afferent meningeal nociceptive neurons, the peripheral arm of the trigeminovascular system, constitutes one of the earliest events promoting the intracranial pain of migraine. However, the link between the varied triggering factors and activation of meningeal nociceptive neurons is not completely understood. Local inflammation with release of mediators from local immune/inflammatory cells is thought to play a critical role in such neuronal response. Meningeal mast cells may play such a role by virtue of their proximity both to meningeal blood vessels and nociceptive axons and their ability to release a host of proinflammatory/algesic mediators. This paper reviews data relevant to the hypothesis that mast cells, upon activation by migraine triggers, contribute to the genesis of migraine headache. Epidemiologic findings, clinical data, and observations on anatomical and physiological characteristics of mast cells converge to suggest an important role of these immune cells in the pathogenesis of migraine. Migraine triggers might directly or indirectly promote mediator secretion from meningeal mast cells, and thereby cause inflammation and activation of the trigeminovascular system. While consistent, the evidence supporting mast cell involvement in the genesis of migraine is largely circumstantial to date. Further studies are needed to test directly the nature of mast cell involvement in the pathogenesis of migraine headache.