Studies of Ebola hemorrhagic fever (EHF) pathogenesis have been hindered by the lack of suitable mouse models that recapitulate key aspects of the disease course in humans. Michael Katze and colleagues (Science 10.1126/science.1259595; 30 October 2014) have now used the Collaborative Cross, a genetically diverse panel of recombinant inbred mice, to identify lines of mice that develop a severe EHF-like pathology following infection with a mouse-adapted strain of Ebola virus (MA-EBOV). The authors infected 47 distinct mouse lines by intraperitoneal injection with MA-EBOV and observed a spectrum of phenotypes ranging from complete resistance to lethal infection with symptoms that included internal hemorrhage, prolonged blood coagulation and severe liver pathology. Further analyses showed that the susceptible lines were characterized by high levels of infectious virus in the spleen and liver, with widespread infection in hepatocytes. Conversely, the resistant lines exhibited low levels of infectious virus, with viral antigen in the liver restricted to endothelial cells and resident macrophages. Genetic mapping studies in these mouse lines will provide insights into the host factors influencing susceptibility to specific phenotypes following Ebola virus infection, which could aid understanding of human disease pathogenesis.