To provide a historic snapshot as regards the evolution of headache treatment throughout the human history, i.e. starting from trepanation to perisutural botulinum toxin (BoNT) injections. Ancient surgeons had aimed to reach the cranium with trepanation (a surgical operation) for headache. As BoNT inhibits the release of nociceptive and pro-inflammatory neuropeptides, it has been recently suggested as an effective alternative in the prophylactic treatment of chronic migraine headache. Chronic migraine is a complex neurological disorder for which the underlying pathophysiology is yet not totally explained. According to the generally accepted hypotheses, peripheral neurogenic activation and central trigeminal sensitization are the two main mechanisms through which its pain develops. Since the headache most commonly occurs around the perisutural areas, and as the primary pathogenesis stem from the meningeal nerve fibers; collateral sensorial branches of the meningeal nerves can be optimal paths to transport BoNT inside the cranium. Concerning the therapeutic efficacy, we anticipate that perisutural injections would be technically challenging with blind techniques and actually possible only if performed under an imaging guidance, e.g. very conveniently with high frequency ultrasound.