Streptococcus pneumoniae (the pneumoccus) is the leading cause of otitis media, community-acquired pneumonia, and bacterial meningitis. The success of the pneumococcus stems from its ability to persist in the population as a commensal and avoid killing by immune system. This chapter first reviews the molecular mechanisms that allow the pneumococcus to colonize and spread from one anatomical site to the next. Then, it discusses the mechanisms of inflammation and cytotoxicity during emerging and classical pneumococcal infections.