Rift Valley fever is a serious emerging viral disease that primarily affects domesticated animals (such as cattle, sheep and goats) and humans. Recurrent outbreaks have been documented in sub-Saharan Africa and have spread outside continental Africa to Madagascar, and the Arabian Peninsula, killing hundreds of thousands of animals and more than a thousand humans. The Rift Valley fever virus, a member of the Bunyaviridae family, genus Phlebovirus, is mainly transmitted by mosquitoes and causes necrotic hepatitis, hemorrhagic fever, and abortions with high mortality among newborn and young animals. Humans can also be infected through aerosols or by physical contact with body fluids, and organs of infected animals. Most patients suffer a self-limiting, febrile illness. However, a subset of patients develop severe forms characterized by hepatitis with fatal hemorrhagic fever, encephalitis or ocular disease. The mortality rate has been reported to vary from 1 to 14 %. Little is known about the natural host factors that influence the progression and severity of Rift Valley fever disease in humans and animals. The large variation in individual response to the infectious agent suggests the existence of host genetic factors influencing susceptibility to Rift Valley fever. At present, it is impossible to dissect host genetic determinants of Rift Valley fever severity in humans and livestock as no one has access to the large numbers of cases required for a genome-wide association study. Animal models of Rift Valley fever disease are needed to perform functional studies in a controlled setting, and to better define genetic susceptibility factors. We are using genetic approaches in the mouse to study the pathogenesis and the genetic factors involved in the severity of Rift Valley fever disease.