Herpes simplex virus infections of the central nervous system are associated with significant morbidity in spite of efficacious antiviral therapy. Herpes simplex virus, type 1 (HSV-1), causes focal neurologic findings that are characteristic of temporal lobe localization. Herpes simplex encephalitis occurs in a biphasic age distribution with one-third of the cases less than 20 and the majority of remaining cases over 50. The diagnostic test of choice is the detection of HSV DNA by PCR in the cerebrospinal fluid. Acyclovir is the treatment of choice and is administered for 14-21 days intravenously at a dose of 10 mg/kg every 8 h. Neonatal HSV infections are more frequently caused by HSV-2 than HSV-1, although the number of cases of the latter is increasing. Infection is most frequently acquired intrapartum by contact with infected maternal genital secretions. Approximately 50 % of all newborns with neonatal infection will have central nervous system involvement. Importantly, HSV-2 infections of the central nervous system in neonates have a poorer outcome than those attributable to HSV-1. Therapy of neonatal infection is achieved with high-dose acyclovir that is administered at 20 mg/kg/every 8 h for 14-21 days. Six months of oral acyclovir post-intravenous treatment has resulted in an improved neurologic outcome for children with central nervous system infection. Likely, in the future, combination antiviral approaches will be employed for both adult and pediatric disease in order to improve neurologic outcome.