Anti-cancer therapy is largely comprised of radiation, surgery, and chemotherapy treatments. Although a single mode of therapy can be effective in treating certain types of cancer, none presents a cure. Multi-modal therapy, the use of two or more agents in combination (e.g., radiation and chemotherapy together), shows potential for a more effective treatment of cancer. The challenge then is identifying effective therapy combinations. In this chapter, we describe the use of Drosophila as a whole animal in vivo model to screen for small molecules that effectively combine with ionizing radiation to kill checkpoint mutants preferentially over wild-type. The differential use of wild-type and checkpoint mutants has the potential to identify molecules that act in a genotype-specific manner to eradicate checkpoint mutant tissues when combined with radiation, while sparing wild-type tissues.