The origins of modern mouse genetics trace back to the mid-1800s, when Gregor Mendel’s experiments with pea plants established the foundational "Law of Inheritance."

In 1909, Clarence Cook Little advanced the field by developing the first inbred mouse strain while studying the coat-color inheritance at Harvard University. His dilute, brown, non-agouti (DBA) strain became the prototype for inbred mouse research. By eliminating genetic variation within a strain, inbred mice allowed researchers to directly link disease phenotypes to specific genotypes, providing a reliable and reproducible model system. Little, along with Leonell Strong, later developed additional cornerstone strains such as C57BL/6, C57BL/6J, A, C3H, and CBA.

In the 1940’s George Snell’s pioneering work on mice led to the discovery of the major histocompatibility complex (MHC, or H2 in mice). To map and study this complex, Snell established multiple congenic mouse lines, many of which remain widely used today. His research laid the groundwork for the field of transplantation immunology and advanced the understanding of cell surface markers.

The 1980s marked a transformative era for mouse genetics. The invention of polymerase chain reaction (PCR), improvements in DNA sequencing through gel electrophoresis, and the creation of the first transgenic mouse revolutionized the field. By the mid-to-late 1980s, techniques such as homologous recombination in embryonic stem cells enabled precise gene targeting, setting the stage for tissue-specific and conditional knockouts, which became widely used tools by the 1990s.

As the use of genetically modified mice expanded, so did the need for preservation and distribution. Recognizing this, the National Institutes of Health (NIH) convened a meeting in March 1998 titled Priority Setting For Mouse Genomics And Genetics Resources. In response to the identified needs and the meeting recommendations, the NIH and the Department of Health and Human Services (DHHS) established the Mutant Mouse Resource & Research Centers (MMRRC) to serve the scientific community and support the growing demand for access to specialized mouse models.

The MMRRC was launched by the NIH’s National Center for Research Resources (NCRR) in 1999, with initial funding through cooperative research agreements that involve development of animal model resources. By May 2001, the MMRRC published its first public website and began accepting submissions of mouse strains. In October 2002, it started distributing mouse models to investigators, providing a centralized resource to advance biomedical research.

Mouse genetics has continued to evolve with the advent of powerful new technologies. SNP arrays and high-throughput sequencing have made genetic analysis faster and more cost-effective. In 2012, the development of CRISPR/Cas9 revolutionized genome editing by enabling precise and efficient DNA modifications. Large-scale initiatives such as Collaborative Cross (CC) and Diversity Outbred (DO) projects introduced mouse populations with genetic diversity comparable to that of humans, broadening their utility in complex trait analysis.

The Knockout Mouse Project (KOMP), coordinated by the International Mouse Phenotyping Consortium (IMPC), continues to produce a comprehensive library of knockout mice, advancing studies of gene function and human disease. Meanwhile, patient-derived xenograft (PDX) models have emerged as vital tools for simulating human tumor biology, offering translational platforms to study cancer progression and evaluate therapies.

Today, the MMRRC has significantly expanded its repository, now housing mice from multiple collections, including embryonic stem cell lines and models from the CC and KOMP projects. As of 2025, the MMRRC maintains over 70,800 repository holdings, underscoring its central role in supporting biomedical research.