The environment and the genetic constitution of both the pathogen and the host influence the severity and the outcome of viral infections. Whereas identification of the host component in humans remains challenging, recent progress in defining genes through analysis of mouse models of infection presenting natural or chemically induced variation in host susceptibility mark a fruitful period of gene discovery. This includes recognition that UNC93B1, which encodes an endocytic protein, is a susceptibility gene, providing an unexpected entry point to our understanding of the response against herpesvirus infection. By contrast, elucidation of alternative mechanisms of host resistance against mouse cytomegalovirus in inbred mouse strains has led to new insights regarding molecular recognition of the infected cells by natural killer cell MHC class I receptors. In addition, the conservation of genetic and functional aspects between mouse and human is enabling a rational pursuit of potential cures. With the continuous development of resources for experimental investigation of the genome, the production of new mutant alleles, and the phenotypic characterization of new models of infection, we predict that mouse genetic models will make an increasing contribution to our understanding of the genetic puzzle of host response to virus infection.