Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Identification of endogenous neuroprotective mechanisms after TBI and the development of therapeutic targets to improve TBI outcomes are areas of intense scientific research. In this review, we summarize genetically modified TBI mouse models and highlight the recent scientific findings from using such models, including mediators of inflammation, programmed cell death and metabolism, modulators of vascular tone and membrane channel proteins. A deeper understanding of the complex biochemical processes and genetic pathways in TBI could offer personalized genomic-based therapies for and improve clinical outcomes in TBI patients.