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With advances in in vivo imaging of fluorescent transgenic mice, combined with fluorescent/bioluminescent bacteria, we can use mouse models to better understand the immune response to these types of infections. By understanding the host and bacterial dynamics within various organ systems, we can develop therapeutics to eliminate these pathogens. This module describes in vivo mouse models of both local and systemic S. aureus infection. © 2021 Wiley Periodicals LLC. Basic Protocol 1 Murine model of Staphylococcus aureus subcutaneous infec