Salmonella enterica is a genetically broad species harboring isolates that display considerable antigenic heterogeneity and significant differences in virulence potential. Salmonella generally exhibit an invasive potential and they can survive for extended periods within cells of the immune system. They cause acute or chronic infections that can be local (e.g. gastroenteritis) or systemic (e.g. typhoid). In vivo Salmonella infections are complex with multiple arms of the immune system being engaged. Both humoral and cellular responses can be detected and characterized, but full protective immunity is not always induced, even following natural infection. The murine model has proven to be a fertile ground for exploring immune mechanisms and observations in the mouse have often, although not always, correlated with those in other infectable species, including humans. Host genetic studies have identified a number of mammalian genes that are central to controlling infection, operating both in innate and acquired immune pathways. Vaccines, both oral and parenteral, are available or under development, and these have been used with some success to explore immunity in both model systems and clinically in humans.