Parenteral therapy of viral infections of the newborn and infant began with vidarabine (adenine arabinoside) for the treatment of neonatal herpes simplex virus (HSV) infections in the early 1980s. Acyclovir has become the treatment of choice for neonatal HSV infections and a variety of other herpesvirus infections. Ganciclovir is beneficial for the treatment of congenital cytomegalovirus (CMV) infections involving the central nervous system (CNS). This article reviews the use of acyclovir and ganciclovir in the treatment of neonatal HSV and congenital CMV infections. A brief summary precedes a detailed discussion of available established and alternative therapeutics. © 2012 Elsevier Inc.