Inbred laboratory mouse strains are used extensively in basic and translational immunology research. However, the commensal and pathogenic repertoire of resident microbes encountered in the wild is not replicated in a lab setting. This can substantially distort how the immune system develops and functions, leading to false assumptions of how our own “wild” immune system works. Rosshart et al. circumvented this dilemma by implanting lab-strain embryos into wild mice (see the Perspective by Nobs and Elinav). The resultant “wildlings” had a systemic immune phenotype and a bacterial, viral, and fungal microbiome much closer to those of their wild counterparts. In two preclinical experiments, where lab mice had previously failed to predict the human response to drug treatments, wildlings accurately phenocopied patient outcomes.