Central nervous system (CNS) infections—i.e., infections involving the brain (cerebrum and cerebellum), spinal cord, optic nerves, and their covering membranes—are medical emergencies that are associated with substantial morbidity, mortality, or long-term sequelae that may have catastrophic implications for the quality of life of affected individuals. Acute CNS infections that warrant neurointensive care (ICU) admission fall broadly into three categories—meningitis, encephalitis, and abscesses—and generally result from blood-borne spread of the respective microorganisms. Other causes of CNS infections include head trauma resulting in fractures at the base of the skull or the cribriform plate that can lead to an opening between the CNS and the sinuses, mastoid, the middle ear, or the nasopharynx. Extrinsic contamination of the CNS can occur intraoperatively during neurosurgical procedures. Also, implanted medical devices or adjunct hardware (e.g., shunts, ventriculostomies, or external drainage tubes) and congenital malformations (e.g., spina bifida or sinus tracts) can become colonized and serve as sources or foci of infection. Viruses, such as rabies, herpes simplex virus, or polioviruses, can spread to the CNS via intraneural pathways resulting in encephalitis. If infection occurs at sites (e.g., middle ear or mastoid) contiguous with the CNS, infection may spread directly into the CNS causing brain abscesses; alternatively, the organism may reach the CNS indirectly via venous drainage or the sheaths of cranial and spinal nerves. Abscesses also may become localized in the subdural or epidural spaces. Meningitis results if bacteria spread directly from an abscess to the subarachnoid space. CNS abscesses may be a result of pyogenic meningitis or from septic emboli associated with endocarditis, lung abscess, or other serious purulent infections. Breaches of the blood–brain barrier (BBB) can result in CNS infections. Causes of such breaches include damage (e.g., microhemorrhage or necrosis of surrounding tissue) to the BBB; mechanical obstruction of microvessels by parasitized red blood cells, leukocytes, or platelets; overproduction of cytokines that degrade tight junction proteins; or microbe-specific interactions with the BBB that facilitate transcellular passage of the microorganism. The microorganisms that cause CNS infections include a wide range of bacteria, mycobacteria, yeasts, fungi, viruses, spirochaetes (e.g., neurosyphilis), and parasites (e.g., cerebral malaria and strongyloidiasis). The clinical picture of the various infections can be nonspecific or characterized by distinct, recognizable clinical syndromes. At some juncture, individuals with severe acute CNS infections require critical care management that warrants neuro-ICU admission. The implications for CNS infections are serious and complex and include the increased human and material resources necessary to manage very sick patients, the difficulties in triaging patients with vague or mild symptoms, and ascertaining the precise cause and degree of CNS involvement at the time of admission to the neuro-ICU. This chapter addresses a wide range of severe CNS infections that are better managed in the neuro-ICU. Topics covered include the medical epidemiology of the respective CNS infection; discussions of the relevant neuroanatomy and blood supply (essential for understanding the pathogenesis of CNS infections) and pathophysiology; symptoms and signs; diagnostic procedures, including essential neuroimaging studies; therapeutic options, including empirical therapy where indicated; and the perennial issue of the utility and effectiveness of steroid therapy for certain CNS infections. Finally, therapeutic options and alternatives are discussed, including the choices of antimicrobial agents best able to cross the BBB, supportive therapy, and prognosis.