The development of antiviral therapy for neonatal herpes simplex virus infection has lead to a significant decrease in mortality and improved morbidity. Vidarabine administered at doses of either 15 mg/kg or 30 mg/kg for ten days leads to 60% overall survival in babies with either central nervous system, CNS, or disseminated disease (n = 59). Babies with CNS disease had a survival rate of 88% compared to those with disseminated disease where survival was only 35%. The introduction of acyclovir into clinical trials has provided the opportunity to further study this disease using a drug with a higher in vitro therapeutic index. While efficacy analyses have not been performed for this ongoing, comparative study, 90% of babies with CNS infection (n = 45) survive as do 65% with disseminated infection (n = 29). Babies with skin, eye, and mouth involvement do well regardless of therapeutic modality. Factors influencing improved treatment are discussed.