Numerous Salmonella typhimurium virulence factors have been identified and characterized using experimental infection of mice. While the murine typhoid model has been used successfully for Salmonella typhi vaccine development and to infer virulence mechanisms important during typhoid fever, information derived from infection of mice has been of limited value in elucidating the mechanisms by which S. typhimurium causes enteritis in humans. Progress in our understanding of virulence mechanisms contributing to diarrheal disease comes from recent studies of bovine enteritis, a S. typhimurium infection, which manifests as acute gastroenteritis. This review compares virulence genes and mechanisms required during murine typhoid, typhoid fever, and bovine enteritis. Comparison of illnesses caused in different animal hosts identifies virulence mechanisms involved in species specific disease manifestations. The determination of the relative importance of virulence factors for disease manifestations in different host species provides an important link between the in vitro characterization of genes and their role during host pathogen interaction.