Salmonella enterica is an intracellular pathogen that colonizes many different host cell types in vivo, including macrophages and epithelial cells. We have shown that Salmonella enterica resides within two distinct compartments in epithelial cells, confined to a membrane-bound vacuole known as the Salmonella-containing vacuole (SCV) and also freely within the cytosol. A subpopulation of internalized bacteria lyse their nascent SCV, leading to bacterial hyper-replication in the epithelial cytosol, transcriptional reprogramming and eventual egress into the gut lumen, providing a potential mechanism of bacterial dissemination. Our research is aimed towards addressing the following outstanding questions: (1) Why do only some Salmonella lyse their vacuole? (2) How does Salmonella lyse its vacuole? and (3) How does Salmonella adapt and survive in the host cell cytosol?