Our recent studies support structural rearrangements in the peptidoglycan (PG) of Salmonella enterica serovar Typhimurium (S. Typhimurium) when this pathogen resides within acidic phagosomes of eukaryotic cells. These changes respond to an intricate regulatory network affecting several of the known PG enzymes as well as novel enzymes that this bacterium acquired during its evolution and are absent in non-pathogenic bacteria. The changes in PG structure occur concomitantly to the activation of virulence factors used by intracellular bacteria to survive inside the phagosomal compartment. Some of the novel PG enzymes up-regulated by intracellular S. Typhimurium bind antibiotics with lower affinity compared to enzymes used by extracellular bacteria. These observations alert us of the necessity for developing new drugs targeting specifically PG biogenesis in the intracellular enviroment and the possibility of immune evasion mechanisms taking place inside the infected cell based on modifications in the PG built by intracellular bacteria.