The term “inverted pathogenicity” stands for the exploitation of microbial toxins, virulence factors and cellular mechanisms for preventive or therapeutic purposes. This mini-review will focus on the major pathogenicity concept of Salmonella and Yersinia and how to use its underlying molecular principle for the development of a novel vaccination strategy. Both bacterial species employ a type III secretion system which mediates secretion and direct delivery (translocation) of antihost factors into the cytosol of eukaryotic cells. One of the best studied type III effector proteins is the 25-kDa Yersinia outer protein E (YopE). During the interaction of Yersinia with professional phagocytes, YopE translocation disturbs eukaryotic cytoskeleton dynamics and inhibits phagocytosis. YopE is a GTPase-activating protein that is active towards G proteins from the Rho family. Fusion of the N-terminal 138 amino acids of YopE comprising the translocation domain of the type III molecule to listeriolysin O (LLO) or p60 of Listeria monocytogenes results in hybrid proteins that are engaged and translocated by both Yersinia and Salmonella type III secretion systems. Oral immunization of mice with attenuated Yersinia or Salmonella vaccine strains expressing translocated chimeric YopE leads to pronounced LLO- or p60-peptide-specific CD8 T-cell responses that confer protective immunity. Surprisingly, cytosolic delivery of YopE/LLO by Yersinia also results in LLO-specific CD4 T-cell priming.