The field of primary headaches and cranial neuralgias has experienced in a relatively brief period a startling progress in expansion of knowledge (1, 2). This has allowed partial unraveling of the machinery involved in the occurrence of attacks and the identification of a set of mediators and genes that are likely to play a role. In the case of migraine, accumulated evidence has very recently led to the development of the first disease-specific prophylactic drug, the CGRP antibodies (3). In other cases, drugs available for indications different from pain, such as botulinum toxin or the antiepileptic drugs, have been tested with adapted protocols proving effective in chronic migraine and showing potential efficacy in other cranial pains, i.e., cluster headache, trigeminal neuralgia, and temporomandibular joint disorder (4, 5). Notwithstanding the undeniable scientific advances, much research is still needed to fully understand and effectively treat primary headaches and cranial neuralgias. Open issues are manifold, spanning from pathophysiology to clinical aspects, and represent exciting challenges for future research.