Zoonotic infections with Salmonella typhimurium (S.Tm) are of serious concern for public health. During the past 100 years, research has identified the pathogen's key virulence factors and established their cellular function. However, in spite of significant efforts we are still lacking effective therapies or vaccines. What have we missed? I would like to discuss, if this failure may root in the striking complexity of the pathogen-microbiota-host interactions which control the infection in vivo. We employ mouse models to approach this and tease apart the roles of the pathogen's virulence factors, the microbiota and the host's innate defenses in the disease. I will use examples from microbiology (i.e. the pathogen's phenotypic diversification in the host's gut) and from immunology (i.e. the inflammasome-based defense of the gut epithelium), to illustrate how we are studying the disease process and how this can lead to the discovery of new general concepts in infection biology.