Brain trauma is a major cause of morbidity and mortality, both in adult and pediatric populations. Much of the functional deficit derives from delayed cell death resulting from induction of neurotoxic factors that overwhelm endogenous neuroprotective responses. To identify the potential molecular mechanisms underlying such delayed responses, we compared gene expression patterns using high-density oligonucleotide arrays at 4, 8, 24, and 72 h after moderate levels of lateral fluid percussion-induced brain injury in rats and lateral controlled cortical impact injury in mice (a total of 47 profiles). Expression of 82 genes in 12 functional categories was significantly changed in both species after trauma. The largest number of gene expression changes were found in the functional groups related to inflammation (17%), transcription regulation (16%), and cell adhesion/extracellular matrix (15%). Fifty percent of genes similarly altered across models had not been previously implicated in traumatic brain injury. Of particular interest were expression changes in genes linked to neurodegeneration, such as ATF3 and lysosomal membrane glycoprotein 2, and to neuroprotection including lipocortin 1, calponin 3, gelsolin, Id-1, and p45 NF-E2. Gene expression profiling across species and models may help identify candidate molecular pathways induced by brain injury, some of which may provide novel targets for therapeutic intervention.