Migraine is a common, neurovascular headache disorder with a complex molecular interplay. The involvement of ion channels in the pathogenesis of migraine gathered considerable attention with the findings that different ion channels subfamilies are expressed in trigeminovascular system, the physiological substrate of migraine pain, and several ion channel openers investigated in clinical trials with diverse primary endpoints caused headache as a frequent side effect. High-conductance (big) calcium-activated potassium (BK_Ca) channel is expressed in the cranial arteries and the trigeminal pain pathway. Recent clinical research revealed that infusion of BK_Ca channel opener MaxiPost caused vasodilation, headache and migraine attack. Thus, BK_Ca channel is involved in pathophysiological mechanisms underlying headache and migraine, and targeting BK_Ca channel presents a new potential strategy for migraine treatment.