Non-typhoid Salmonella strains containing virulence plasmids are highly associated with bacteremia and disseminated infection in humans. These plasmids are found in Salmonella serovars adapted to domestic animals, such as Salmonella dublin and Salmonella choleraesuis, as well as in the widely distributed pathogens Salmonella typhimurium and Salmonella enteritidis. Although virulence plasmids differ between serovars, all contain a highly conserved 8-kb region containing the spv locus that encodes the spvR regulatory gene and four structural spvABCD genes. Studies in mice suggest that the spv genes enhance the ability of Salmonella strains to grow within cells of the reticuloendothelial system. The spv genes are not expressed during exponential growth in vitro but are rapidly induced following entry of Salmonella strains into mammalian cells, including macrophages. Transcription of the spv genes is controlled by the stationary-phase (T factor RpoS, and mutations in RpoS abolish virulence. These studies suggest that the ability of Salmonella strains to respond to starvation stress in the host tissues is an essential component of virulence.