We have been using the flavivirus tick-borne encephalitis virus (TBEV) as a model system for investigating the molecular mechanisms underlying the membrane fusion process mediated by a class II viral fusion protein, the flavivirus envelope protein E. In the mature virion this protein exists as a metastable dimer that dissociates at the acidic pH in endosomes and is converted into a more stable trimeric conformation. The dimer dissociation step liberates an internal fusion peptide that interacts with the target endosomal membrane, and then further conformational changes are believed to drive membrane fusion. Although flavivirus fusion appears to be a more facile and efficient process than that of alphaviruses, which also possess a class II viral fusion protein, the fusion mechanism in both viral systems involves structurally related interactions with lipids, specifically the 3beta-hydroxyl group at C3 of cholesterol. The class II viral fusion machineries are structurally different from those involving class I viral fusion proteins, such as those found in orthomyxoviruses, paramyxoviruses, retroviruses, and filoviruses, but have certain similarities in common with bacterial pore-forming proteins.