The genetic influences on the course of mycobacterial infections during epidemics and in endemic areas have always been suspected, but the precise nature of such genetic control and of the inherited mechanisms of susceptibility have been unknown. We have used methods of population genetics in the mouse to discover a single dominant autosomal gene (Bcg), which controls the susceptibility to various species of mycobacteria as well as to other intracellular parasites. The phenotypic expression of the Bcg gene has been defined as nonspecific macrophage activation for bactericidal function, resulting in the destruction of ingested intracellular parasites early following infection. Using recombinant inbred strains of mice, we have mapped this gene to the centromeric part of chromosome 1 and we have created a high resolution linkage map and, subsequently, a physical map in the close vicinity of this locus. A 400 kb bacteriophage and cosmid contig assembled within the genomic interval overlapping Bcg contained six novel transcription units. RNA expression studies showed that one of these genes (designated Nramp for "natural resistance associated macrophage protein"), was expressed exclusively in macrophages. Nramp encodes an integral membrane protein that has structural homology with known prokaryotic and eukaryotic transport systems, suggesting a macrophage-specific membrane transport function. Susceptibility to infection (Bcgs) in 27 Bcgs and Bcgr strains tested is associated with a Gly-105 to Asp-105 substitution within predicted transmembrane domain 2 of Nramp, making this gene a strong candidate for Bcg. The chromosomal segment in the vicinity of the Bcg gene has been conserved in the human genome (chromosome 2q). Linkage analysis between the phenotype of disease during a tuberculosis outbreak in an extended multisib Canadian Indian family and allelic variants of chromosome 2 has revealed a significant LOD score. This finding, together with the emerging information on almost total sequence homology between the murine and human Nramp genes suggests that this gene may be responsible for the phenotype of resistance or susceptibility to tuberculosis.