Here we conducted the first comparative study of S. Typhimurium proteomic remodeling within macrophages versus epithelial cells. In addition to many shared features, our data revealed proteomic signatures highly specific to one type of host cells. Notably, intracellular S. Typhimurium differentially regulates the two type III secretion systems (T3SSs) far quicker in macrophages than in epithelial cells, so do bacterial flagellar and chemotaxis systems degenerate. Importantly, our comparative analysis uncovered vast induction of histidine biosynthesis in macrophages but not in epithelial cells, which is attributed to differing levels of intracellular histidine as well as defective biosynthetic pathways of this amino acid.