As the focus of human genetics shifts from Mendelian traits to complex diseases, a sophisticated genetic tool kit—with space for genetics (classical, molecular, statistical, and quantitative), metabolics, proteomics, bioinformatics, and mathematics—is required to elucidate their multifactorial traits and regulatory processes. Importantly, mouse resources optimized to study the actions of isolated genetic loci on a fixed background are insufficient on their own for studying intact polygenic networks and genetic interactions, and researchers must work in the context of experimental model systems that optimally mimic the genetic structure of human populations. The success of such phenogenomic approaches depend on the efficacy by which specific mutations (gene targeting) and variability (recombinant inbreeding) can be introduced into the mouse genome, and on the optimization of phenotyping analyses of the mutant mouse lines. This unit describes the basic genetic approaches used to in the study of mouse model systems