Epidemiologic trends causing infections of the nervous system remain a significant source of morbidity and mortality one half-century after the introduction of penicillin. This article outlines common causes of bacterial meningitis, aseptic meningitis syndrome, encephalitis, abscess, spinal cord syndromes, and cranial and peripheral nerve problems. Recommendations for diagnostic evaluation and both empiric and definitive antimicrobial therapy are offered; controversial management issues are also discussed. The protean manifestations of varicella-zoster virus and Lyme diseases are outlined. In addition, special considerations in the immunocompromised host, including organ transplant recipients, cancer patients, and HIV-positive persons are explained, and antimicrobial therapy is discussed.