Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

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