Herpes simplex virus (HSV) infections in newborns are associated with severe disease and death. Trials conducted by the Collaborative Antiviral Study Group have established the standard of care for the treatment of neonatal HSV disease with marked improvements in morbidity and mortality. We review the studies that have contributed to our understanding of the epidemiology and clinical course of neonatal HSV disease and discuss the landmark trials that have resulted in safe and effective treatment together with improved diagnostics. Although significant advances have been made, neonatal HSV disease continues to have an unacceptably high mortality rate with significant sequelae in survivors. Further research is urgently needed for prevention.