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Wolbachia are widespread endosymbiotic bacteria that manipulate the reproduction of arthropods through a diversity of cellular mechanisms. In cytoplasmic incompatibility (CI), a sterility syndrome originally discovered in the mosquito Culex pipiens , uninfected eggs fertilized by sperm from infected males are selectively killed during embryo development following the abortive segregation of paternal chromosomes in the zygote. Despite the recent discovery of Wolbachia CI factor (cif) genes, the mechanism by which they control the fate of paternal chromosomes at fertilization remains unknown. Here, we have analyzed the cytological distribution and cellular impact of CidA and CidB, a pair of Cif proteins from the Culex -infecting Wolbachia strain w Pip. We show that expression of CidB in Drosophila S2R+ cells induces apoptosis unless CidA is co-expressed and associated with its partner. In transgenic Drosophila testes, both effectors colocalize in germ cells until the histone-to-protamine transition in which only CidB is retained in maturing spermatid nuclei. We further show that CidB is similarly targeted to maturing sperm of naturally infected Culex mosquitoes. At fertilization, CidB associates with paternal DNA regions exhibiting DNA replication stress, as a likely cause of incomplete replication of paternal chromosomes at the onset of the first mitosis. Importantly, we demonstrate that inactivation of the deubiquitylase activity of CidB does not abolish its cell toxicity or its ability to induce CI in Drosophila. Our study thus demonstrates that CI functions as a transgenerational toxin-antidote system and suggests that CidB acts by poisoning paternal DNA replication in incompatible crosses. [Display omitted] • CidA and CidB function as a toxin-antidote system in Drosophila S2R+ cells • CidA and CidB associate in male germ cells until mid-spermiogenesis • The CidB toxin is loaded into sperm nuclei in transgenic flies and infected Culex • In eggs, CidB associates with replication stress markers on paternal chromosomes Wolbachia -mediated cytoplasmic incompatibility (CI) is an insect sterility syndrome controlled by the protein effectors CidA and CidB. By characterizing the distribution and impact of CidA and CidB in Drosophila and Culex mosquitoes, Horard et al. demonstrate that CidA and CidB function as a transgenerational toxin-antidote system to mediate CI. [ABSTRACT FROM AUTHOR]