Arboviruses, or arthropod-borne viruses, such as West Nile virus, Dengue virus, and Zika virus, pose a serious threat to public health worldwide. West Nile virus was introduced to the United States in 1999, and is now endemic, causing over 2,000 domestically acquired cases in the U.S. annually in mammals. Similarly, dengue and Zika viruses are endemic in the Americas and pose novel threats to the human population. Tick-borne viruses such as Powassan virus and Heartland virus are increasing in frequency in the U.S. At this time, there is no commercially available vaccine or therapeutic to treat these viral infections. Because nearly every mammalian case of these virus infections originates from the insect vector, it is imperative that we also understand viral pathogenesis, transmission, and the immune response in insect models as well as pathogenesis and the host responses in infected mammals. The development of methods to block arbovirus transmission from the vector may be effective at ceasing arthropod-to-human infection since the current recommendation to prevent these viral infections is to decrease contact with mosquitoes. Additionally, improving our understanding of epidemiology and ecology will also help develop measures to reduce virus spread. In order to better study mammalian and insect host responses to infection, a number of genetic tools are available, such as fly, mosquito, and tick models, recombinant viruses, mouse models, and bioinformatics tools. The studies described in this eBook will illustrate host responses to infection using mammalian and insect models, identify critical signaling nodes of the innate immune response, and discuss virus transmission from insect to mammal or among infected hosts. Taken together, these studies will elucidate means of decreasing infections in human populations and provide potential targets for future study and therapeutic design.