Neonatal herpes simplex virus (HSV) infection usually is acquired during the birth process, as the neonate comes in contact with the virus during passage through an infected birth canal. After an incubation period which can last as long as 2 to 4 weeks, neonatal HSV disease then manifests in 1 of 3 ways: (1) disseminated disease, with visceral organ involvement (including infection of the brain in two-thirds to three-quarters of patients); (2) central nervous system disease (with no other visceral organ involvement, but with skin lesions in two-thirds of patients); or (3) disease limited to the skin, eyes, and/or mouth (ie, SEM disease). Diagnostic advances in recent years have focused primarily on applying polymerase chain reaction technology to babies suspected of having neonatal HSV disease. Treatment of neonatal HSV disease with intravenous acyclovir has improved the likelihood of survival substantially, although neurologic morbidity remains a common sequelae, especially among survivors of central nervous system disease. Despite these advances, the duration of time from onset of symptoms and initiation of antiviral therapy has remained unchanged for the past 20 years. The surest way to improve outcomes rapidly at this point is to raise awareness of neonatal HSV disease, resulting in the establishment of earlier diagnoses and more rapid institution of antiviral therapy. In the longer term, development of a bedside nucleic acid detection kit for real-time detection of HSV DNA in the maternal genital tract at the time of delivery could identify which babies are at risk of developing neonatal HSV disease. © 2005 Elsevier Inc. All rights reserved.