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The task of cataloging human genetic variation and its relation to disease is rapidly approaching completion. The new challenge is to discover the function of disease-associated genes and to understand the pathways that lead to human disease. We propose that achieving this new level of understanding will increasingly rely on the use of model organisms. We discuss the advantages of the mouse as a model organism to our understanding of human disease.The collection of available mouse strains represents as much genetic and phenotypic variation as is found in the human population. However, unlike humans, mice can be subjected to experimental breeding protocols and the availability of tissues allows for a far greater and deeper level of phenotyping. New methods for gene editing make it relatively easy to create mouse models of known human mutations. The distinction between genetic and epigenetic inheritance can be studied in great detail. Various experimental protocols enable the exploration of the role of the microbiome in physiology and disease.We propose that there will be an interdependence between human and model organism research. Technological advances and new genetic screening platforms in the mouse have greatly improved the path to gene discovery and mechanistic studies of gene function.