Meningoencephalitis describes any process that results in the inflammation of both the meninges and the brain parenchyma. Underlying triggers for the development of meningoencephalitis can be infectious, autoimmune, vasculitic, neoplastic, or metabolic in origin. Patients who develop infectious meningoencephalitis typically present with fevers, headache, vomiting, nuchal rigidity, and signs of neurologic dysfunction, including altered mental status, seizures, or focal neurologic deficits. Pathogens that should be considered as potential causes of meningoencephalitis vary by patient risk factors, exposure history, and geographic location. Neurotropic viruses account for the vast majority of cases, some with clear geographic distributions (e.g., Japanese encephalitis virus) and others that are ubiquitous (e.g., herpes simplex viruses). A thorough history and physical examination can help to guide the diagnostic evaluation, although in many cases, the specific pathogen is never identified. Expert, supportive neurointensive care should be provided for all patients with meningoencephalitis. In addition, the parenteral administration of the antiviral medication, acyclovir, reduces the morbidity and mortality associated with herpes simplex virus meningoencephalitis when the infection is identified early and treatment initiated without delay. As such, intravenous acyclovir should be administered empirically to all patients with a clinical diagnosis of viral meningoencephalitis until infection with herpes simplex virus has been ruled out. Specific antimicrobial treatment for most other causes is not available.