A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between either the tick or mosquito vector to small mammals (e.g. rodents, skunks) and reptiles to non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continue to be reported. In addition to in humans, viral persistence can also be established in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines in culture. Although a considerable amount of research has focused on the potential roles of defective virus particles, autophagy and/or apoptosis induced evasion of the immune response, the precise mechanism of flavivirus has yet to be elucidated. In this review, we present findings that aid in further understanding of how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in viral persistence, the development of relevant animal models of viral persistence, and investigating the host responses that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral–host relationships in wildlife animals and could be used to elucidate the mechanisms for the establishment of viral persistence in these animals.