The ability of macrophages to become activated is central to antimicrobial immunity. Microbial stimuli can elicit a cascade of gene-inductive events mediating inflammation, elimination of the invading organism and induction of T-cell memory against reinvasion. Nramp1, a gene originally identified as Ity/Lsh/Bcg for its role in controlling Salmonella typhimurium, Leishmania donovani and Mycobacterium bovis infections in mice, regulates this cascade. Here we examine how the structure of the Nramp1 protein might relate to its function, and how variable expression of the human homologue (NRAMP1) might mediate enhanced resistance to infection but cause susceptibility to autoimmune disease.