AbstractStandardized phenotypic analysis of mutant forms of every gene in the mouse genome will provide fundamental insights into mammalian gene function and advance human and animal health. The availability of the human and mouse genome sequences, the development of embryonic stem cell mutagenesis technology, the standardization of phenotypic analysis pipelines, and the paradigm‐shifting industrialization of these processes have made this a realistic and achievable goal. The size of this enterprise will require global coordination to ensure economies of scale in both the generation and primary phenotypic analysis of the mutant strains, and to minimize unnecessary duplication of effort. To provide more depth to the functional annotation of the genome, effective mechanisms will also need to be developed to disseminate the information and resources produced to the wider community. Better models of disease, potential new drug targets with novel mechanisms of action, and completely unsuspected genotype–phenotype relationships covering broad aspects of biology will become apparent. To reach these goals, solutions to challenges in mouse production and distribution, as well as development of novel, ever more powerful phenotypic analysis modalities will be necessary. It is a challenging and exciting time to work in mouse genetics. WIREs Syst Biol Med 2012, 4:547–563. doi: 10.1002/wsbm.1183This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Organismal Models Physiology > Physiology of Model Organisms