Laboratory studies of Ebola virus infection have suffered from a lack of mouse models that recapitulate some of the pathology seen in humans, such as Ebola haemorrhagic fever (EHF). Using genetically diverse mouse strains from the Collaborative Cross project, Rasmussen and Okumura et al. found a range of susceptibilities to Ebola virus, from resistant mouse strains to those that were susceptible and showed many of the known human pathologies. The authors also identified host genetic and transcriptional signatures that correlate with infection severity. This study paves the way for further detailed mouse studies of Ebola virus infection and may inform both the genetic determinants of Ebola virus susceptibility in humans and possible therapeutic approaches to limit pathogenesis.