Central nervous system (CNS) infections continue to be an important cause of mortality and morbidity. Current strategies for prevention and therapy of CNS infection are compromised by incomplete understanding of the microbial-host interactions that contribute to its pathogenesis and emergence of antimicrobial-resistant microorganisms. Our development of successful strategies in prevention and treatment of bacterial meningitis requires multifactorial concepts and approaches, which include advances in vaccinology, epidemiology of meningitis, emergence of antimicrobial-resistant pathogens, knowledge of pharmacokinetics and pharmacodynamics of antimicrobial agents, as well as the pathogenesis of meningitis. Prevention of bacterial meningitis targeting microbes has been effective, such as vaccination. The introduction of the protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis has changed the epidemiology of bacterial meningitis. Antimicrobial chemoprophylaxis is efficacious in prevention against H. influenzae type b and N. meningitidis meningitis. Suspected bacterial meningitis is a medical emergency and requires empiric antimicrobial therapy without delay, but recognition of pathogens with increasing resistance to antimicrobial agents is an important factor in selection of empiric antimicrobial regimen. A more complete understanding of the microbial-host interactions that are involved in the pathogenesis of CNS infections and associated neurologic sequelae is likely to help in developing new strategies for prevention and therapy of CNS infection.