Patricelli, Janes, and colleagues identified a small-molecule covalent inhibitor of mutant KRAS^G12C, ARS-853, that selectively bound to the GDP-bound, inactive protein and prevented formation of the GTP-bound state. ARS-853 blocked downstream mutant KRAS–driven signaling via the MAPK and PI3K pathways and inhibited the growth of KRAS^G12C-mutant cells. KRAS^G12C rapidly cycled its nucleotide state, allowing for effective binding of ARS-853, and KRAS^G12C-GTP levels were regulated by upstream signaling factors, suggesting that combined targeting of upstream activators may enhance the efficacy of single-agent KRAS^G12C inhibition. These findings indicate that ARS-853 blocks oncogenic KRAS^G12C signaling and has promise as a potential therapeutic for KRAS^G12C-mutant cancer. For details, please see the article by Patricelli, Janes, and colleagues on page 316.