Mendelian susceptibility to mycobacterial disease is a recently described entity, responsible for disseminated disease due to nonvirulent mycobacteria and, to a lesser extent, non-typhoid salmonella in otherwise healthy patients. Different mutations in 5 genes and allelic heterogeneity accounts for 12 different diseases. The proteins encoded by the mutated alleles all belong to the interferon gamma/ìnterleukin 12 loop, a hallmark of granulomatous immune response. Patients with defects in the IFNgamma pathway are predisposed to mycobacterial diseases, while those with defects in the IL-12 pathway are threatened more often by non-typhoid (systemic) salmonellosis. Tuberculosis has been described in both of these signaling pathway defects. Genetic dissection of the IL-12/IFNgamma pathway should improve our understanding of the human immune response to mycobacteria and help us begin to elucidate the genetic bases of tuberculosis.