Headache mechanisms: what we still do not know

Primary headaches such as migraine, cluster headache (CH), and tension-type headache (TTH) are highly prevalent neurological disorders with complex and heterogeneous pathophysiology. Traditionally attributed to either vascular or neuronal origins, current evidence supports a neurovascular model involving dynamic interactions between the nervous system and cranial. This Perspective examines the role of two key neuropeptides – calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) – in the generation of primary headaches. CGRP is a validated target in migraine, but its clinical utility is limited by biomarker instability and a significant proportion of non-responders. PACAP is emerging as a complementary target, though its receptor mechanisms remain incompletely understood. While neither CGRP nor PACAP appear to play a major role in TTH, their contribution to migraine and CH highlights the need for precision approaches based on molecular endophenotypes. Understanding these mechanisms may inform the development of more effective, personalized headache treatments.