Numerous observations have established a crucial role for phagocytic cells in host resistance to Salmonella. Activated macrophages rely on a complex array of oxygen-dependent antimicrobial molecules to inhibit or kill intracellular Salmonella. An initial oxidative bactericidal phase, which is dependent on the respiratory burst phagocyte oxidase (phox) is succeeded by a prolonged nitrosative bacteriostatic phase, which is dependent on inducible nitric oxide synthase (iNOS). The sequential contribution of phox and iNOS to anti-Salmonella innate immunity has been demonstrated both in vitro and in vivo. The temporal progression from the predominant production of reactive oxygen species to the production of nitrogen oxides could optimize the initial reduction in microbial burden while minimizing the immunopathological consequences of the host inflammatory response.