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The minimal genetic requirements for microbes to survive within multiorganism communities, including host-pathogen interactions, remain poorly understood. Here, we combined targeted gene mutagenesis with phenotype-guided genetic reassembly to identify a cooperative network of SPI-2 T3SS effector genes that are sufficient for Salmonella Typhimurium (S Tm) to cause disease in a natural host organism. Five SPI-2 effector genes support pathogen survival within the host cell cytoplasm by coordinating bacterial replication with Salmonella -containing vacuole (SCV) division. Unexpectedly, this minimal genetic repertoire does not support S Tm systemic infection of mice. In vivo screening revealed a second effector-gene network, encoded by the spv operon, that expands the life cycle of S Tm from growth in cells to deep-tissue colonization in a murine model of typhoid fever. Comparison between Salmonella infection models suggests how cooperation between effector genes drives tissue tropism in a pathogen group. [Display omitted] • Genome reconstruction reveals essential SPI-2 effector genes of Salmonella • A five-gene network (θ genes) coordinates SCV division and Salmonella proliferation • θ genes and the spv operon cooperate to induce typhoid fever in mice • Host-tissue tropism is determined by diverse effector-gene networks The minimal effector-gene repertoire required for Salmonella intracellular survival and infection of host tissues remains undefined. In this work, Chen et al. performed a systematic interrogation of the SPI-2 effector genome to identify a minimal gene network that drives cellular and tissue tropism in the Salmonella enterica pathogen group. [ABSTRACT FROM AUTHOR]