Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this talk I will highlight new opportunities for targeting KRAS mutant tumors through inhibition of MAPK signaling with conformation-specific kinase inhibitors. The role of RAF dimerization and interaction with RAS is central to this strategy. Further I will discuss how kinase dependent and independent functions of RAF isoforms, particularly CRAF, are important in RAS-driven tumors. Mechanistic studies shed light on the role of CRAF kinase independent functions, highlighting novel drugging strategies to treating RAS mutant tumors that are also CRAF dependent.