Flaviviruses are arthropod-borne viruses, several of which represent emerging or re-emerging pathogens responsible for widespread infections with consequences ranging from asymptomatic seroconversion to severe clinical diseases and congenital developmental deficits. This variability is due to multiple factors including host genetic determinants, the role of which has been investigated in mouse models and human genetic studies. In this review, we provide an overview of the host genes and variants which modify susceptibility or resistance to major mosquito-borne flaviviruses infections in mice and humans.