The combination of classical mouse genetics with mouse models derived from transgenic and gene-targeting technologies provides new opportunities to elucidate the functional roles of genes in normal and disease processes. Candidate disease genes can be systematically inactivated and tested individually or in combination with other mutations, alleles, or transgenes. Such new mouse models can also be examined in the context of different strain backgrounds that are relevant to the field of study. In our studies we have demonstrated how the combined effect of multiple gene knockout mutations involved in DNA repair and cell-cycle progression can be examined in classical tumor-induction protocols. The goal of this chapter is to serve as a guide for investigators who may be relatively new to the field of mouse genetics, but are interested in utilizing this vast and expanding resource in lung cancer research.