Encephalitis is a serious neurologic condition that frequently results in long-term neurologic complications. Effective management in adults with suspected infectious encephalitis involves testing the cerebrospinal fluid for common pathogens, including herpes simplex virus-1, varicella-zoster virus, enteroviruses, and West Nile virus. Early initiation of high-dose intravenous acyclovir is recommended. Epidemiologic clues and immune status of the host should be considered when attempting to identify the cause of encephalitis. When no cause is identified, next-generation sequencing or a brain biopsy may be warranted. Further research should focus on developing new therapeutic options for this challenging clinical syndrome.