Systemic Salmonella enterica infections are a major cause of mortality worldwide and are becoming increasingly untreatable. Recent single-cell data from a mouse model of typhoid fever show that the host immune system actually eradicates many Salmonella cells, while other Salmonella organisms thrive at the same time in the same tissue, causing lethal disease progression. The surviving Salmonella cells have highly heterogeneous metabolism, growth rates, and exposure to various stresses. Emerging evidence suggests that similarly heterogeneous host-pathogen encounters might be a key feature of many infectious diseases. This heterogeneity offers fascinating opportunities for research and application. If we understand the mechanisms that determine the disparate local outcomes, we might be able to develop entirely novel strategies for infection control by broadening successful host antimicrobial attacks and closing permissive niches in which pathogens can thrive. This review describes suitable technologies, a current working model of heterogeneous host-Salmonella interactions, the impact of diverse Salmonella subsets on antimicrobial chemotherapy, and major open questions and challenges.