Tuberculosis remains a significant public health problem: one-third of the human population is infected with virulent Mycobacterium tuberculosis (MTB) and 10% of those are at risk of developing tuberculosis during their lifetime. In both humans and experimental animal models, genetic variation among infected individuals contributes to the outcome of infection. However, in immunocompetent individuals (the majority of patients), genetic determinants of susceptibility to tuberculosis remain largely unknown. Mouse models of MTB infection, allowing control of exposure and other potential environmental contributors, have proven extremely useful for examining this genetic component. In a cross of C3HeB/FeJ (susceptible) by C57BL/6J (resistant) inbred mouse strains, we have previously identified one major genetic locus, sst1, the susceptible allele of which did not confer an overt immunodeficiency, but rather specifically affected progression of lung tuberculosis. Having generated and tested the sst1 congenic strains, we have observed that this locus only partially explained the difference in susceptibility of the parental strains to MTB. We now present further studies controlling for the effect of the sst1, identify four additional tuberculosis susceptibility loci and characterize their effects by testing an independent cross, knockout or congenic mice.