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Laboratory mice have been instrumental in drug discovery, but there are important limitations to their translational research value. Although these issues are mainly due to the genetic differences between mice and humans, the environmental conditions of lab mice — especially regarding pathogen exposure and microbiota — also have an impact. Now, reporting in Science, Rosshart et al. have generated mice with an immune phenotype and microbiome that resemble those of mice in natural environments, which they show could provide more realistic disease models.