A major challenge facing mammalian genetics over the next decade is the systematic and comprehensive annotation of mammalian gene function. As part of the International Knockout Mouse Consortium, several programmes are ongoing to generate conditional mutants for all mouse genes. An even greater challenge will be the determination of phenotypic outcomes for each mutation and the identification of disease models. The International Mouse Phenotyping Consortium (IMPC, www.impc.org) is undertaking the development of a comprehensive Catalogue of Mammalian Gene Function. The IMPC incorporates 20 major mouse centres around the world that undertake mouse production and phenotyping. The IMPC programme has two phases: Phase 1, 2011-2016, is approaching completion and will deliver the phenotypes of around 5000 mouse mutant lines; Phase 2 from 2016-2021 will undertake the analysis of the remaining genome. IMPC centres operate a core, standardised, broad-based adult phenotyping pipeline encompassing the major biological and disease systems, including gross pathology and tissue collection as a mandatory requirement. Many centres have also begun to employ a standardised embryonic phenotyping pipeline to analyse the many homozygous lethals, incorporating an assessment of time of lethality and morphological defects. In addition, lacZ expression data is being collected for adult organs and E12.5 embryos. All data from each production and phenotyping centre is uploaded to a central Data Coordination Centre (DCC), and following QC and analysis is archived and disseminated to the wider biomedical sciences community along with appropriate annotation tools. In the first 4 years of the programme, nearly 8000 ES cell lines have been injected, over 5000 mouse mutant lines generated and phenotype data from nearly 3500 mutants collected at the DCC. We will describe many new insights into the genetic and molecular bases of disease, report the generation of numerous novel disease models, and elaborate a fundamental appraisal of the pleiotropic landscape of mammalian gene function.