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Successful treatment strategies for patients with traumatic brain injury (TBI) remain elusive despite standardised clinical treatment guidelines, improved understanding of mechanisms of cellular response to trauma, and a decade of clinical trials aimed at identifying therapeutic agents targeted at mediators of secondary injury.The information explosion relative to mechanisms of secondary injury has identified several potential targets for intervention. Depending on the type of injury to the brain and the intensity and the success of resuscitation, necrosis, apoptosis, inflammatory and excitotoxic cellular damage can be seen. These same processes may continue postinjury, depending on the adequacy of clinical care. Each of these mechanisms of cellular damage can initiate a cascade of events mediated by endogenous signals that lead to secondary neurological injury.Several factors contributed to the failure of earlier clinical trials. Now that these have been recognised, a positive impact on future drug development in TBI has been realised. Both the US and Europe have organised brain injury consortiums where experts in the treatment of TBI provide insight into study design, implementation, conduct and oversight in conjunction with the pharmaceutical industry. Consequently, future clinical trials of new investigational treatments have greater potential for identifying therapies of merit in specific populations of patients with TBI.Pharmacological strategies under investigation are targeting sites involved in the secondary cascade that contribute to overall poor outcome following the primary injury. These treatments include ion channel antagonists including calcium channel antagonists, growth factors, antioxidants, stem cells, apoptosis inhibitors, and inhibitors of other signal modulators.In conclusion, the complexity of TBI pathology and the mechanisms contributing to secondary injury present unique therapeutic challenges. Appropriate research targets for intervention continue to be investigated, however, the likelihood of improving outcomes with a single approach is extremely small. There is a need for collaborative efforts to investigate the optimal time for drug administration and the logical sequence or combination of treatments that will ultimately lead to improved neurological outcomes in this population.