The flaviviruses comprise a large genus of medically important arthropod-transmitted, enveloped viruses. Flaviviruses cause a variety of human diseases ranging from mild febrile illnesses to severe hemorrhagic manifestations (yellow fever [YF], dengue [DEN]; Monath 2001; Guzman and Kouri 2002) or meningo-encephalitic syndromes (Japanese encephalitis [JE], Saint Louis encephalitis [SLE], West Nile [WN] fever and tickborne encephalitis [TBE]; Gould 1999; Igarashi 1999; Porterfield 1999; Brinton 2002) (Table 1). DEN, JE and YF viruses are the most significant human viral pathogens transmitted by mosquitoes. WN fever has been an emerging problem in Europe, in the Middle East, and more recently in the United States (Brinton 2002). The natural life cycles of vector-borne flaviviruses involve complex relationships among arthropod vectors, reservoirs, and mammalians. Knowledge of the molecular interactions between virus and its host cells are of particular importance for the understanding of flavivirus pathogenicity. Flaviviruses can replicate lytically in a variety of mammalian cells and cytopathic effects appear to be due to the induction of apoptosis. The purpose of this review is to summarize what is presently known about the molecular signaling mechanisms and viral components that contribute to flavivirus-induced apoptosis.