Mouse models are essential for virtually every aspect of biomedical research. A recent NIH analysis indicates that as many as 71% of NIH R01 awards may use mouse models. The Knockout Mouse Project (KOMP) and the International Knockout Mouse Consortium (IKMC) were successful in generating conditional knockout (cKO) ES cell clones for nearly 90% of genes; however, only about 25% of these were converted into mice by 2013, the year when CRISPR technologies affected the workflow at KOMP/IKMC centers. Subsequently, very rapid CRISPR/Cas9-based technologies that bypass ES cells were widely adopted for generating simple KO mice, but proved difficult for cKO models. To solve this problem, we developed Easi-CRISPR, in which single- stranded DNA donors with short homology arms substitute for double-stranded DNA donors with long homology arms. Because Easi-CRISPR is simple, rapid, and efficient, and has proved reproducible at multiple loci in multiple laboratories, many groups, including KOMP laboratories, have adopted our method. To extend the success of breakthrough technologies like Easi-CRISPR, we propose to solve much bigger problems that are universal to projects using mouse models. Some examples of these challenges are; (1) reducing the excessive amount of time spent in breeding Cre-LoxP models; (2) addressing the limited availability of Cre driver lines; (3) developing CRISPR-based technologies for knock-out first models, the most elegant and versatile design used at KOMP centers in the ES cell era, and; (4) creating cKO alleles for “difficult-to-target” genes, including those with single exons or unusually long exons, and genes with repetitive sequences, which together comprise about 15% of all protein coding genes. Having worked on many aspects of mouse genetics; as a researcher designing and breeding models for my own work, as a transgenic core director advising hundreds of investigators on the best mouse model options for their research, and as a developer of breakthrough technologies to move the field forward—my experience helped to identify these key problems in the field. Using the Genomic Innovator award, I will solve each of these problems by developing innovative technologies along the lines of Easi-CRISPR. Successful completion of this project will benefit individuals designing mouse models through their core facilities and will also allow KOMP/IKMC centers to produce the most generally useful models. Given the very high use of mouse models, developing technologies to address such universal problems is expected to have a major impact on all fields of biomedical research in the future.