The management of traumatic brain injury (TBI) is challenging and there is a need for neuroprotective therapies. A better understanding of the pathomechanism of TBI, particularly of the evolution of secondary damage, is providing targets for new approaches and selected ones in clinical development are described. Clinical trials that have been discontinued in the past for lack of efficacy or other reasons are also listed. One of the problems has been the translation of promising animal experimental results into clinically successful therapies. The complexity of sequelae of TBI requires a multifaceted approach. In addition to the investigation of drugs for neuroprotective effect in TBI, new technologies based on cell/gene therapies, biomarkers and nanobiotechnology are being employed for the integration of neuroprotection with neuroregeneration and are promising.