Traumatic brain injury is one of the most common causes of death in childhood. Traditionally, the engineering and medical communities have assumed that children respond as miniature adults, which influences protective equipment design, clinical practice guidelines for treatment, and the diagnostic distinction of violence-related injuries from unintentional injuries. However, by integrating biomechanical information derived from computational models and instrumented dolls with patient data and animals models, our lab has determined that mechanisms of severe brain injury actually vary with the age of the child. Infants, toddlers, and pre-adolescent children have different responses to brain injuries due to changes in tissue mechanical properties and thresholds for neural and vascular injury that occur during maturation. We have developed the only immature animal model that recreates the constellation of diffuse brain injuries seen in children and have used it to correlate rapid head accelerations with histopathological, functional (behavior, cognition, motor), and metabolic responses after mild, severe, and repeated head injuries. We have measured region- and age-dependent variations in brain and skull properties and the large strain nonlinear behavior and macroscopic anisotropy of brain tissue, which have had a profound impact on computational models of the head. We have illuminated the role that direction of head rotational acceleration during injury plays in the resulting physiology, behavior, and pathology. Our work has provided direct translational benefit by supplying guidelines for sedation and cerebral perfusion pressure support to be used for best therapeutic efficacy after brain injury. Current studies investigate new therapeutic interventions and best clinical management practices in acute and chronically injured animals. In a field filled with social, medical, and legal controversy, our research program is redefining the paradigm of traumatic brain injury mechanisms and treatment in children.