Context-dependent biological variation presents a unique challenge to the reproducibility of results in experimental animal research, because organisms’ responses to experimental treatments can vary with both genotype and environmental conditions. In contrast to the current gold standard of rigorous standardization in experimental animal research, the authors recommend the use of systematic heterogenization of study samples and conditions by actively incorporating biological variation into study design through diversifying study samples and conditions. In this article, the scientific rationale for this approach is provided so that researchers, regulators, funders and editors can understand this paradigm shift. In addition, a road map towards better practices in view of improving the reproducibility of animal research is presented.