The lack of monitoring biomarkers for severe traumatic brain injury (TBI) represents a critical barrier to monitoring individual patient response to promising neuroprotective therapies. Severe TBI remains a disabling and life-threatening injury that affects approximately more than one million individuals worldwide each year. To date, all efficacy trials of neuroprotective agents for treating TBI have failed, despite demonstrated promise in early phase trials. Proposed reasons for these failures include the lack of mechanistic early end-points that make a thorough evaluation of different doses and treatment schedules feasible at a reasonable cost. Monitoring blood-based biomarkers may be useful in this regard. They are measured serially, are important for assessing the presence/status/extent of a disease and for monitoring its response to a therapeutic intervention. Our long-term objective is to improve TBI outcomes by identifying blood-based biomarkers that allow real time monitoring of individual patient response to promising therapies.