Abstract: Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Despite significant medical advances over recent decades, many survivors of TBI develop long term neuro-cognitive deficits. Previously, only moderate and severe injuries were thought to account for the devastating consequences of TBI. However, there is increasing evidence that even milder injuries may result in problematic lifelong cognitive and affective disturbances. TBI is typically characterized by an an acute physical injury followed by a protracted innate neuro-inflammatory response. These reponses, mediated via neuronal, astrocyte and microglial cells, amongst others, and may result in widespread neuronal death and a micro-environment that is not conducive to brain repair (Manivannan et al., 2021). Whilst the primary physical injury often evades intervention from a medical perspective, the subsequent neuro-inflammatory response offers a potential therapeutic target. Nonetheless, effective pharmacological strategies continue to elude clinicians and scientists due to the complex underlying pathogenesis and difficulties of modelling such a heterogeneous disease. However, the majority of research to date has focused on investigating the effects of post-traumatic neuro-inflammation on grey matter injury rather than the consequences upon white matter (WM), which contributes greatly to cognitive dysfunction across many neurological diseases (Filly and Kelly, 2018). Herein, we will briefly discuss: (i) high mobility group box protein 1 (HMGB1) as a potential therapeutic target; (ii) the relevance of WM injury in TBI and current understanding of WM repair following injury; and (iii) perspectives on how HMGB1 may play a role.