The ability to modify central host cellular functions is a major advantage to many bacterial pathogens that use such strategies as part of their virulence mechanisms. Small GTPases, including Rho GTPases, make particularly attractive targets for pathogens because of their central roles in modulating cellular functions such as cytoskeletal control. Such modifications of these GTPases can include direct chemical modification of the GTPase or interfacing with some of the regulatory elements associated with GTPase control. Pathogens use these alterations in GTPase functions for a variety of functions, including killing the host cell, mediating bacterial uptake into the host cell (invasion), reprogramming actin to form a lesion in host cells underlying adherent bacteria, to mediate intracellular survival by affecting intracellular trafficking, or to provide polymerized actin mechanisms to propel microbes around inside host cells and into adjacent cells. Collectively, these examples represent many key microbial virulence mechanisms that have led to a much deeper understanding of both microbial pathogens and GTPase functions.