Large (big)-conductance calcium-activated potassium (BKCa) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BKCa channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BKCa channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BKCa channels and ATP-sensitive potassium (KATP) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BKCa channel activation can provoke migraine in migraine patients, and whether the BKCa channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BKCa channel openers or blockers in migraine patients are needed.