Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis worldwide. Despite optimal antibiotic therapy and supportive care, the mortality of this condition remains very high at 20-30% in the developed world and over 60% in under-resourced hospitals. In developed countries, approximately half of the survivors suffer intellectual impairment, hearing loss, or other neurological damage. There is an urgent need for more information about the mechanisms of brain damage and death in pneumococcal meningitis so that new treatments can be designed. Using proteomic techniques and bioinformatics, the protein content of cerebrospinal fluid can be examined in great detail. Animal models have added greatly to our knowledge of possible mechanisms and shown that hippocampal apoptosis and cortical necrosis are distinct mechanisms of neuronal death. The contribution of these pathways to human disease is unknown. Using proteomic techniques, neuronal death pathways could be described in CSF samples. This information could lead to the design of novel therapies to minimize brain damage and lower mortality. This minireview will summarize the known pathogenesis of meningitis, and current gaps in knowledge, that could be filled by proteomic analysis.