Bacterial infection results in a dynamic interplay between the pathogen and its host. The underlying interactions are multilayered, and the cellular responses are modulated by the local environment. The intestine is a particularly interesting tissue regarding host-pathogen interaction. It is densely colonized by commensal microbes and a portal of entry for ingested pathogens. This necessitates constant monitoring of microbial stimuli in order to maintain homeostasis during encounters with benign microbiota and to trigger immune defenses in response to bacterial pathogens. Homeostasis is maintained by physical barriers (the mucus layer and epithelium), chemical defenses (antimicrobial peptides), and innate immune responses (NLRC4 inflammasome), which keep the bacteria from reaching the sterile lamina propria. Intestinal pathogens represent potent experimental tools to probe these barriers and decipher how pathogens can circumvent them. The streptomycin mouse model of oral Salmonella enterica serovar Typhimurium infection provides a well-characterized, robust experimental system for such studies. Strikingly, each stage of the gut tissue infection poses a different set of challenges to the pathogen and requires tight control of virulence factor expression, host response modulation, and cooperation between phenotypic subpopulations. Therefore, successful infection of the intestinal tissue relies on a delicate and dynamic balance between responses of the pathogen and its host. These mechanisms can be deciphered to their full extent only in realistic in vivo infection models.