Approximately 350,000 individuals in the US are affected annually by severe and moderate traumatic brain injuries (TBI) that may result in long-term disability. This rate of injury has produced ~ 3.3 million disabled survivors in the US alone. There is currently no specific treatment available for TBI other than supportive care, but aggressive prehospital resuscitation, rapid triage, and intensive care have reduced mortality rates. With the recent demonstration that neurogenesis occurs in all mammals (including man) throughout adult life, albeit at a low rate, the concept of replacing neurons lost after TBI is now becoming a reality. Experimental rodent models have shown that neurogenesis is accelerated after TBI, especially in juveniles. Two approaches have been followed in these rodent models to test possible therapeutic approaches that could enhance neuronal replacement in humans after TBI. The first has been to define and quantify the phenomenon of de novo hippocampal and cortical neurogenesis after TBI and find ways to enhance this (for example by exogenous trophic factor administration). A second approach has been the transplantation of different types of neural progenitor cells after TBI. In this review the authors discuss some of the processes that follow after acute TBI including the changes in the brain microenvironment and the role of trophic factor dynamics with regard to the effects on endogenous neurogenesis and gliagenesis. The authors also discuss strategies to clinically harness the factors influencing these processes and repair strategies using exogenous neural progenitor cell transplantation. Each strategy is discussed with an emphasis on highlighting the progress and limiting factors relevant to the development of clinical trials of cellular replacement therapy for severe TBI in humans.