Japanese encephalitis causes serious health problems in countries in Southeast Asia, where the causative virus is endemic. Whereas most adults living in this region have acquired immunity, children are at high risk of infection. Childhood mass immunization programs with first-generation mouse brain-derived vaccines efficiently reduced Japanese encephalitis incidence in affected countries, but immunization recommendations have mostly been abolished in Japan owing to the occurrence of severe side effects. Thus, there is a pressing need for safer vaccines to keep the disease under control. The safety profile of the current vaccines, together with the relatively low incidence, makes the risk/benefit ratio unfavorable for immunization of travelers to Southeast Asia, despite the high mortality once the clinical disease has developed. As Asian countries become increasingly popular travel destinations, the availability of well-tolerated vaccines would likely shift the ratio towards immunization. Currently, there is one second-generation inactivated cell-culture-grown vaccine in late-stage clinical development that is approaching licensing in developed countries.