A number of inbred lines of chickens have been shown to be resistant or susceptible to systemic salmonellosis caused by Salmonella enterica serovar Gallinarum in adult birds, or by S. enterica serovar Enteritidis and S. enterica serovar Typhimurium in young chicks. Resistant lines show only moderate pathology and low mortality rates, whereas susceptible lines display extensive pathological changes and higher levels of mortality following Salmonella infection. Genetic resistance to salmonellosis is dominant and not linked to sex, MHC or Slc11a1 (formerly known as Nramp1), which leads to resistance in mice and other species. A novel locus encoding resistance to salmonellosis has been identified on chicken chromosome 5, and designated SAL1. The nature of the differences in pathology found between resistant and susceptible chicken lines in vivo indicates that resistance is expressed at the level of the mononuclear phagocyte system. Macrophages from adult resistant line birds cleared Salmonella serovar Gallinarum from infected macrophages within 24 h, whereas Salmonella bacteria persisted within macrophages from susceptible line birds for at least 48 h. Clearance of Salmonella by macrophages was accompanied by a strong and reproducible respiratory burst response in resistant lines, but little or no response in susceptible lines. Macrophages from an outbred chicken line showed variable responses. No differences were seen in macrophage nitric oxide production in cells from resistant or susceptible lines. These differences suggest that increased macrophage antimicrobial activity correlates with resistance and that macrophage activity plays an important role in genetic resistance to systemic salmonellosis in the chicken.