OBJECTIVE: To present a state-of-the-art review of mechanisms of secondary injury in the evolution of damage after severe traumatic brain injury in infants and children. DATA SOURCES: We reviewed 152 peer-reviewed publications, 15 abstracts and proceedings, and other material relevant to the study of biochemical, cellular, and molecular mechanisms of damage in traumatic brain injury. Clinical studies of severe traumatic brain injury in infants and children were the focus, but reports in experimental models in immature animals were also considered. Results from both clinical studies in adults and models of traumatic brain injury in adult animals were presented for comparison. DATA SYNTHESIS: Categories of mechanisms defined were those associated with ischemia, excitotoxicity, energy failure, and resultant cell death cascades; secondary cerebral swelling; axonal injury; and inflammation and regeneration. CONCLUSIONS: A constellation of mediators of secondary damage, endogenous neuroprotection, repair, and regeneration are set into motion in the brain after severe traumatic injury. The quantitative contribution of each mediator to outcome, the interplay between these mediators, and the integration of these mechanistic findings with novel imaging methods, bedside physiology, outcome assessment, and therapeutic intervention remain an important target for future research.