Over the past six years, many new agents have become available for the treatment of bacterial central nervous system (CNS) infections. Certain principles guide the use of these agents for CNS infections: first, an antimicrobial agent must be able to penetrate the CNS to be effective; second, the CNS is a "relatively immunoincompetent site" so that an antimicrobial must achieve levels within the CNS capable of killing the offending bacterium. The lack of efficacy of chloramphenicol for meningitis due to gram-negative aerobes is probably due to its failure to achieve such killing levels, whereas the success of the newer cephalosporins, such as cefotaxime and ceftriaxone, is due to their very high killing activity against these organisms. Penicillin remains the first choice for pneumococcal and meningococcal meningitis. Ampicillin plus chloramphenicol is still recommended as initial therapy for meningitis due to Hemophilus influenzae. The newer cephalosporins are now the first choice for the treatment of meningitis due to many gram-negative bacilli. Trimethoprim-sulfamethoxazole may also be useful in some of these infections and those due to Listeria monocytogenes. In the treatment of severe CNS infections, a team approach is advised to ensure optimal therapy.