The article discusses the challenges and lessons learned from clinical trials in traumatic brain injury (TBI). TBI remains a significant public health issue, with high incidence rates and long-term disabilities. Despite promising preclinical data, many recent clinical trials have failed to show significant improvements in outcomes. The National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop to review previous trials and identify key insights for future studies. Key points include the need to understand specific mechanisms of cellular injury, the importance of adequate pharmacokinetics and drug binding, and the impact of intercenter variability. The article also highlights the failure of several promising drugs, such as Selfotel, Cerestat, and D-CPP-ene, due to various reasons including inadequate preclinical testing, protocol design issues, and treatment timing. Steroids and nimodipine have shown mixed results, with no clear beneficial effect on outcomes. The article emphasizes the importance of protocol adherence, centralized CT scan assessment, and the need to target elevated intracranial pressure (ICP) as a primary endpoint. It also discusses the role of subarachnoid hemorrhage (SAH) and the importance of stratifying patients based on CT scan findings. Overall, the workshop provided valuable insights for improving the design and conduct of future TBI clinical trials.The article discusses the challenges and lessons learned from clinical trials in traumatic brain injury (TBI). TBI remains a significant public health issue, with high incidence rates and long-term disabilities. Despite promising preclinical data, many recent clinical trials have failed to show significant improvements in outcomes. The National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop to review previous trials and identify key insights for future studies. Key points include the need to understand specific mechanisms of cellular injury, the importance of adequate pharmacokinetics and drug binding, and the impact of intercenter variability. The article also highlights the failure of several promising drugs, such as Selfotel, Cerestat, and D-CPP-ene, due to various reasons including inadequate preclinical testing, protocol design issues, and treatment timing. Steroids and nimodipine have shown mixed results, with no clear beneficial effect on outcomes. The article emphasizes the importance of protocol adherence, centralized CT scan assessment, and the need to target elevated intracranial pressure (ICP) as a primary endpoint. It also discusses the role of subarachnoid hemorrhage (SAH) and the importance of stratifying patients based on CT scan findings. Overall, the workshop provided valuable insights for improving the design and conduct of future TBI clinical trials.