Salmonella infections can cause a range of intestinal and systemic diseases in human and animal hosts. Although some Salmonella serovars initiate a localized intestinal inflammatory response, others use the intestine as a portal of entry to initiate a systemic infection. Considerable progress has been made in understanding bacterial invasion and dissemination strategies, as well as the nature of the Salmonella-specific immune response to oral infection. Innate and adaptive immunity are rapidly initiated after oral infection, but these effector responses can also be hindered by bacterial evasion strategies. Furthermore, although Salmonella resides within intramacrophage phagosomes, recent studies have highlighted a surprising collaboration of CD4 Th1, Th17, and B-cell responses in mediating resistance to Salmonella infection.