Infections with many Gram-negative pathogens rely on type III secretion system effectors. We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network which can tolerate significant contractions; this was tested in vivo using the mouse pathogen Citrobacter rodentium (encoding 31 effectors). Progressive gene deletions showed that effector essentiality for infection is context dependent and that the network can tolerate 60% contraction while maintaining pathogenicity. Despite inducing drastically different colonic cytokine profiles (e.g. IL-22, IL-17, IFN-γ or GM-CSF), different networks induced protective immunity. Using data from >100 distinct mutant combinations, we built and trained an in silico model able to predict colonization outcomes, which were confirmed experimentally. Furthermore, reproducing the human-restricted enteropathogenic E. coli effector repertoire in C. rodentium was not sufficient for efficient colonization, implicating effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses.