Large consanguineous pedigrees, controlled environments, and genetically defined inbred strain backgrounds afforded by the laboratory mouse provide significant advantages for the discovery of Mendelian disease genes. The mouse as a disease model also offers the advantages of highly orthologous protein coding genes and mammalian physiology. Until the advent of high throughput sequencing, the rate of Mendelian disease gene discovery in both the human and mouse genomes was comparatively slow. Taking advantage of the world’s largest collection of mouse strains with naturally occurring Mendelian disease phenotypes, we are using whole exome sequencing (WES) to discover naturally occurring disease mutations at unprecedented rates. To date, we have found over 90 new disease causing alleles. Over 80% of these alleles are in genes that have been implicated with Mendelian disease in the human population and an additional 10% are in genes that are novel, and, until recently, had yet to be associated with a mouse phenotype or human disease. These data demonstrate that even after nearly 100 years of research, spontaneously arising Mendelian mutations in the mouse genome continue to yield new discoveries. Despite our unprecedented rate of spontaneous mutation discovery, 50% of our cases remain unsolved using a standard exome sequencing analytics pipeline. Using a combination of approaches, we have found evidence that a large fraction of unsolved exome cases likely involve structural mutations that span exons but escape detection by standard exome pipelines. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing. To advance our Mendelian disease modeling efforts we are integrating our disease allele discovery with parallel human Mendelian disease efforts by the Baylor-Hopkins Center for Mendelian Genomics (BHCMG). This integrated approach not only informs unsolved human exome cases, it also provides clinical information that we are using to implement disease relevant phenotyping and in some cases, the development of precise models through gene editing. We will provide several examples of new disease gene associations and mouse models including Diamond Blackfan anemia, Charcot-Marie-Tooth disease, Maffucci syndrome and idiopathic learning disability.