Neonatal HSV is most commonly transmitted at the time of delivery with the risk being dramatically higher if the mother has first-episode genital HSV and does not have an elective Cesarean section. Maternal HSV type-specific serology can be used to differentiate first-episode from recurrent infection in this setting, allowing for use of empiric acyclovir for the highest risk infants. There is a need for new strategies as current methods of prevention of transmission of HSV to neonates have limited effectiveness, as they do not account for the fact that the majority of transmission occurs from asymptomatic women. After transmission has occurred, early recognition of neonatal HSV improves the prognosis. Diagnosis needs to be considered in all infants who develop vesicles, unexplained seizures, or possible sepsis in the first 5 weeks of life.