Many viruses are capable of infecting the central nervous system of neonates; however, herpes simplex virus (HSV) is among the most severe and has significant mortality and morbidity associated with it. Fortunately, HSV is treatable with the commercially available antiviral drug acyclovir. Neonatal HSV infection is usually acquired in the peripartum period, which increases the likelihood that antiviral therapy can be beneficial since viral damage is of a relatively short duration compared with injury to the developing fetal brain from viruses such as rubella, cytomegalovirus, and Zika virus that primarily are acquired in utero. Studies conducted over several decades have advanced our knowledge of the impact of antiviral therapy on neonatal HSV disease outcomes. Consequently, many neonates now are effectively treated and experience no or lesser long-term sequelae of this potentially devastating infection.