Macrophages are the first line of defense against microbial pathogens; they recognize microbial structures and products via surface receptors and intracellular antigen sensors. Engagement of surface receptors results in phagocytosis of the microbe into a specialized vacuole, the phagosome. Through a series of fusogenic events, the phagosome matures into a microbicidal phagolysosome that is highly acidic and contains a number of degradative enzymes and toxic molecules that cause destruction of the microbe. Salmonella typhimurium (S. typhimurium) and Legionella pneumophila (L. pneumophila) are two pathogenic Gram-negative bacteria that are able to block phagosome maturation. The hypothesis is that the macrophages response to these pathogens contains a common as well as a pathogen-specific response. Genome-wide transcription profiling approach was used to compare macrophage responses to phagocytosis of S. typhimurium or L. pneumophila at early time points, 2h and 4h post-infection. This book highlights the importance of comparing the response to different bacterial infections in order to better understand the innate immunity mechanisms and should be useful for scientist in the field