ABSTRACT The introduction of clinical exome sequencing and whole genome sequencing has transformed our ability to diagnose patients with suspected genetic disease. Clinical exome sequencing identifies a potential molecular DNA lesion in at least 25-30% of patients with a suspected genetic diagnosis. New technologies such as genome sequencing, mRNA sequencing, and metabolomics profiling are continuing to increase this diagnostic rate. In addition, the introduction of these technologies has led to the discovery of hundreds of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to structure, function and mechanistic discoveries that point to personalized approaches for management and therapy. Moreover, a precise genetic diagnosis ends the costly diagnostic odyssey, facilitates personalized preventive medicine for long-term complications of the diagnosis, enables appropriate anticipatory guidance, and facilitates genetic counseling for families. However, up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or because the clinical significance of variants identified in genomic studies remains unclear. Collaborations between clinician scientists and model organism researchers have played a fundamental role in facilitating this revolution in genomic medicine. Model organisms, such as the fruity fly and laboratory mouse, are important tools for aiding in the interpretation of variants identified in sequencing data. In some cases, model organisms have provided key data supporting the association of a phenotype with a new disease gene. Beyond modeling the genotype and phenotype, studies in model organisms, such as fly, mouse, and non-human primates, may inform therapeutic management of patients with genetic disorders. In addition, these model organisms provide key resources for biomarker discovery, drug screens, and evaluation of genotype-specific therapeutic strategies. Our previous success in precision modeling of human disease at BCM is due to strong collaborative efforts between local clinicians, genome scientists, and model organism scientists that is afforded by the integration of basic, translational, clinical, and diagnostic activities housed within the DMHG at BCM. This integration has established a flow of clinical and genomic information from prenatal, pediatric and adult genetics patients and study participants to laboratory geneticists at Baylor Genetics and various gene discovery programs. In so doing, we have established and modeled the clinical, preclinical, and model organism workflow that we are now extending to mammalian species. Our Preclinical/Co-Clinical section will leverage this existing infrastructure and expertise and extend its use to the wider community through the following aims: 1) Coordinate and review variant nominations, 2) Formulate clinical questions requiring precision modeling, and 3) Translate clinical significance of precision models.