In the past few years, an important question in microbiology has arisen from reports indicating that several pathogenic bacteria have evolved virulence factors directed towards a Ras subfamily of GTPases, namely the Rho GTPases. Progress made in studying both the virulence factors and the signaling pathways involving Rho GTPases has shed light on this crosstalk. One central question is raised by the findings that both activating and inactivating virulence factors that target Rho GTPases coexist in some pathogenic bacteria. Further studies on this peculiar aspect of the bacteria-host cell interactions, which leads to the outbreak of infectious diseases, might clarify whether this aspect of Rho GTPase activation or inactivation represents a finely adapted response of the pathogen for its own benefit or might lead to a reaction of the host against the bacteria.