These data highlight how the interaction of viral antagonists like the NS5 proteins of flaviviruses influenced STAT2 evolution in mammals, the barriers to evolving NS5 resistance, the impacts of STAT2 antagonism on flavivirus species tropism, and offer a road map for overcoming hurdles to the creation of immunocompetent small animal models of flavivirus infection. The gene discussed is RAF1; the disease is Flavivirus Infections.