The path to building a better mouse model starts with the microorganisms that colonize it. According to a new study, lab mice born with natural microbiota and pathogens may provide greater translational research value for immunology than widely used, traditional laboratory animals - something the study authors demonstrated in two preclinical drug studies involving their engineered mice. In many ways, the tiny laboratory mouse is the quintessential hero of biomedical research; generations of mice have served as invaluable models in the quest to better understand human health and immunology, and untold millions owe their health to medical treatments that began as a simple test in a tiny mouse. However, as a translational model, the laboratory mouse is far from perfect. Most successful preclinical studies in mice fail to transition into human bedside practice, Stephan Rosshart and colleagues emphasize. Recent studies have shown that inbred strains of laboratory mice lack the "wild" range of microbiome diversity, which could greatly distort an accurate portrayal of natural immune system function. To address these shortcomings and build a more relevant mouse model, Rosshart and colleagues implanted lab-strain embryos into wild mice to create "wildlings" - mice that harbor the same diverse bacterial, viral and fungal communities as wild mice, but also maintain the genetic uniformity of laboratory animals. To evaluate the translational potential of the wildling model, Rosshart et al. recreated two preclinical drug studies using wildling mice where lab mice had previously failed. The results show that wildling mice more accurately predicted human response to the drugs and could have prevented failed clinical trials in both cases. "Due to the resemblance of the wildling microbiome to that of humans, wildling mice will likely provide a an elegant and more robust preclinical model to predict success in human clinical trials," write Samuek Nobs and Eran Elinav in a related Perspective.