It is clear that there is genetic variation among different individuals in their susceptibility to infection by viruses and other pathogens. Identification of the genes involved in conferring resistance or susceptibility to viral infection will allow us to understand both mechanisms of infection and pathogenesis and to develop reagents for treating or preventing them. Because of the large number of genetically well-characterized inbred mouse strains and the ability to generate targeted germ line mutations, this species is particularly well-suited for such analysis. This review focuses on how the use of genetics to study the retrovirus mouse mammary tumor virus allowed the dissection of both the viral infection pathway and the response of the host to this infection.