Flaviviruses are arthropod-borne pathogens that cause significant disease on all continents of the world except Antarctica. Flavivirus diseases are particularly important in tropical regions where arthropod vectors are abundant. Live-attenuated virus vaccines (LAVs) and inactivated virus vaccines (INVs) exist for some of these diseases. LAVs are economical to produce and potent, but are not suitable for use in the immunocompromised. INVs are safer, but are more expensive to produce and less potent. Despite the success of both classes of these first-generation flavivirus vaccines, problems associated with their use indicate a need for improved products. Furthermore, there are no suitable vaccines available for important emerging flavivirus diseases, notably dengue and West Nile encephalitis (WNE). To address these needs, new products, including LAVs, INVs, viral-vectored, genetically engineered LAVs, naked DNA, and subunit vaccines are in various stages of development. Here we describe the current state of these first- and second-generation vaccine candidates, and compare these products to our recently described single-cycle, encapsidation defective flavivirus vaccine: RepliVAX. RepliVAX can be propagated in C-expressing cells (or as a unique two-component virus) using methods similar to those used to produce today's economical and potent LAVs. However, due to deletion of most of the gene for the C protein, RepliVAX cannot spread between normal cells, and is unable to cause disease in vaccinated animals. Nevertheless, RepliVAX is potent and efficacious in animal models for WNE and Japanese encephalitis, demonstrating its utility as a third-generation flavivirus vaccine that should be potent, economical to produce, and safe in the immunocompromised. © 2008 Elsevier Inc. All rights reserved.