TBI is considered "the most complex disease in our most complex organ". It is characterized by great heterogeneity in terms of etiology, mechanisms, pathology, severity, and treatment, with widely varying outcomes. Falls and high velocity road traffic incidents cause different types of injury. TBI may consist of diffuse damage, contusional brain damage (bruises) or intracerebral hematoma. Structural abnormalities may or may not be visible on imaging. The clinical severity ranges from minor (minimal complaints, no visible structural damage) to virtually unsurvivable. We have found large differences in outcome between centres with up to a six fold higher risk in "poorer" vs. "better" centres after adjustment for chance effects and case mix. We now also recognize that TBI is not just an acute event, but can trigger a chronic process, with progressive injury over hours, days, weeks, months, and even years. Whilst basic research has increased our knowledge of the mechanisms involved, improvements in clinical management have not kept pace. Guidelines for the treatment of TBI are available (BTF; www.nice.org.uk) but the evidence underpinning these recommendations is weak. Moreover, current approaches to the characterization of disease severity and outcome are uni-dimensional and have not undergone refinement for more than three decades. Clinical research in TBI is particularly challenging due to disease heterogeneity, and has been further hampered by dispersion of efforts with little collaboration between researchers in acute and post-acute settings, and by research that focuses on isolated disease mechanisms and tests highly specific neuroprotective agents in underpowered clinical trials. Indeed, improvements in TBI care have come not from clinical trials, but rather from observational studies, expert guideline development and meta-analysis of individual patient data. However, the large scale international observational studies on TBI in Europe and the USA that underpin these improvements date back at least 20 years and do not reflect current clinical care.