Neonatal herpes simplex virus (HSV) infection is one of the life-threatening infections of newborns. It affects approximately 1,500 to 2,200 infants per year in the United States. Changes in the presentation of neonatal HSV infection over the past two decades include an increase in the frequency of skin, eye, and mouth (SEM) disease with a relatively unchanged rate of central nervous system (CNS) disease, but a relative decline in disseminated infection. Although the mortality of neonatal HSV infections has declined with current antiviral therapy, the mortality rate in CNS disease (15%) and disseminated disease (57%) remains high. Morbidity has been seen most frequently in infants with CNS and disseminated disease, with seizures or infection with HSV-2 determined to be risk factors for poor outcome in survivors. In a multicenter, randomized, blinded study by the Collaborative Antiviral Study Group, no differences in outcome were seen between neonates treated with vidarabine and acyclovir. More recently, administration of oral acyclovir has been demonstrated to prevent cutaneous recurrences of HSV after neonatal SEM disease. Although promising, this investigational protocol requires further evaluation before a routine recommendation for prophylactic therapy with oral acyclovir can be made. The application of polymerase chain reeaction to rapid diagnosis of neonatal HSV disease may provide additional information on which clinical decisions may be based, but its diagnostic utility outside the research setting is still unproven. Further clinical trials for prophylaxis of recurrent SEM disease, prophylactic therapy for the prevention of recurrences of CNS or disseminated disease, the appropriate use of rapid diagnostic testing, and future therapies that may include passive antibody plus antiviral therapy or higher dosage and longer duration of antiviral therapy need to be evaluated.