Abstract Ever since RAF was shown to be a key downstream effector of RAS in the early 90s, RAF inhibition has been a goal within the drug discovery community. Sorafenib, an early entrant to the RAF armamentarium, was discovered through biochemical RAF inhibition assays with the goal of disrupting RAS signaling. Anticancer efficacy that was demonstrated through clinical trials was likely through “off-target” inhibition of VEGF receptors, and RAF is not effectively inhibited in RAS-mutant tumor cells. Furthermore, BRAF-mutant tumors were also poorly targeted by sorafenib, most likely because the “type 2” binding mode is ineffective against the activated BRAF kinase. Subsequently, compounds such as vemurafenib, dabrafenib, and encorafenib were developed as “type 1” inhibitors that target the active form of BRAF kinase: these inhibitors show efficacy in many BRAF-mutant tumors. Curiously, these RAF inhibitors cause certain side effects that have been attributed to the “RAF inhibitor paradox”: the ERK pathway is paradoxically stimulated by RAF inhibitors in cells with an activated RAS pathway. To overcome this liability, the next generation of RAF inhibitors dubbed “paradox breakers” were developed. As a BRAF-specific dimer disruptor, PLX8394 selectively inhibits ERK signaling in tumors bearing both monomer- and dimer-dependent BRAF mutants, including BRAF fusions and splice variants, while sparing RAF function in normal cells and avoiding paradoxical ERK activation in RAS-mutant cells. A converse effort seeks to take advantage of the paradox to identify RAS cell liabilities. By hyperstimulating the ERK pathway, “paradox activators” could tip the balance in favor of cellular disharmony. Future efforts exploiting this mechanism will enhance the context for thinking about RAF and near-neighbor targets in RAS tumors and guide the judicious selection of combination therapies involving RAF-targeting agents and other therapeutics. Citation Format: Ying Zhang, Gideon Bollag. Interplay between RAF inhibitors and RAS [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA32.