Specific local brain responses, influenced by parasite sequestration and host immune system activation, have been implicated in the development of cerebral malaria. This study assessed whole-brain transcriptional responses over the course of experimental cerebral malaria by comparing genetically resistant and susceptible inbred mouse strains infected with Plasmodium berghei ANKA. Computational methods were used to identify differential patterns of gene expression. Overall, genes that showed the most transcriptional activity were differentially expressed in susceptible mice 1 to 2 days before the onset of characteristic symptoms of cerebral malaria. Most of the differentially expressed genes identified were associated with immune-related gene ontology categories. Further analysis to identify interaction networks and to examine patterns of transcriptional regulation within the set of identified genes implicated a central role for both interferon-regulated processes and apoptosis in the pathogenesis of cerebral malaria. Biological relevance of these genes and pathways was confirmed using quantitative RT-PCR and histopathological examination of the brain for apoptosis. The application of computational biology tools to examine systematically the disease progression in cerebral malaria can identify important transcriptional programs activated during its pathogenesis and may serve as a methodological approach to identify novel targets for therapeutic intervention.