Previous advances in the genetics of infectious diseases derived principally from identification of single genes and their isolated effects on the progression of infection. Modern genetic analysis represents a powerful means of understanding the interplay among different pathways activated in the course of infection, their hierarchy and interactions in terms of the development of an optimal protective strategy. By utilizing both whole-genome scanning of (C3HxC57BL/6)F2 and a set of the recombinant congenic strains, produced by backcrossing B10 onto a C3H background, we demonstrated that susceptibility to tuberculosis is a multigenic trait. We have identified two distinct groups of susceptible mice: one that dies within four to six weeks of infection (supersusceptible) and another that dies within seven to 10 weeks (comparable to the susceptible parental strain). Our preliminary genetic analysis suggests that the susceptibilty of those groups is controlled by different genetic factors. Supersusceptible mice exhibit dramatic lung pathology, not observed in either parental strain, and their survival after infection with virulent Mycobacterium tuberculosis is comparable to that of mice rendered immunodeficient by disruption of essential immune genes. Further genetic and functional analyses of these strains offer possibilities for understanding the control of transmission, preferential growth of the pathogen in the lung, and mechanisms of local and systemic protective immune responses.