Many human pathogens use a type III secretion system to translocate effectors that can functionally be divided into signaling, disabling, and countervirulence effectors. Among the signaling effectors are those that activate Rho GTPases, which play a central role in coordinating actin dynamics. However, many pathogens also translocate effectors with antagonistic or counteractive functions. For example, Salmonella translocates SopE and SptP, which sequentially turn Rac1 and Cdc42 on and off. In this paper, we show that enteropathogenic E. coli translocates EspH, which inactivates mammalian RhoGEFs and triggers cytotoxicity and at the same time translocates the bacterial RhoGEFs EspM2 and EspT, which are insensitive to EspH, and so neutralizes EspH-induced focal adhesion disassembly, cell detachment, and caspase-3 activation. Our data point to an intriguing infection strategy in which EPEC and EHEC override cellular Rho GTPase signaling by disabling mammalian RhoGEFs and replacing them with with bacterial RhoGEFs that promote cell adhesion and survival.