Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other infections in the central nervous system can mimic HSE. Support for the diagnosis from a neurodiagnostic perspective is aided by the demonstration of disease of the temporal lobe by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the gold standard for establishing diagnosis is the detection of herpes simplex virus DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and far more desirable than brain biopsy, false negatives can occur early after disease onset. Current therapeutic management calls for the administration of acyclovir at 10 mg/kg every 8 hours for 21 days. Even with early administration of therapy after the onset of disease, nearly two thirds of survivors will have significant residual neurologic deficits. Recent investigative efforts are assessing the value of PCR detection of viral DNA at the completion of therapy and the value of prolonged antiviral therapy. © 2005 Elsevier Inc. All rights reserved.