We are defining principles governing synthetic lethality. My lab is discovering mechanisms for activating cell death specifically in tumor cells harboring a specific oncogenic mutation. This approach, inspired by synthetic lethal screening in model organisms, is used to illuminate gene function. We demonstrated that we can discover compounds with genotype-selective lethality by screening 70,000 compounds for those that display oncogenic-RAS-selective lethality. We have found six such compounds, one of which (erastin) we found to act through mitochondrial proteins to cause oxidative, non-apoptotic death. This is the first example of a genotype-selective compound and mechanism discovered using synthetic lethal screening. These studies reveal novel proteins and pathways involved in cell death, principles governing synthetic lethality and novel functions of oncogenes and tumor suppressors.