This study investigates the role of the KEAP1-NRF2 pathway in non-small-cell lung cancer (NSCLC). KEAP1 negatively regulates NRF2 activity by targeting it for proteasomal degradation, but biallelic inactivation of KEAP1 is a common event in NSCLC. The authors found that somatic mutations in KEAP1 were present in 50% of lung cancer cell lines and 19% of tumor samples, with all mutations occurring in highly conserved amino acid residues. These mutations likely abolish KEAP1 repressor activity. Loss of KEAP1 function leads to increased nuclear accumulation of NRF2, resulting in enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. This study demonstrates that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC, suggesting that tumor cells manipulate the NRF2 pathway to survive chemotherapy.This study investigates the role of the KEAP1-NRF2 pathway in non-small-cell lung cancer (NSCLC). KEAP1 negatively regulates NRF2 activity by targeting it for proteasomal degradation, but biallelic inactivation of KEAP1 is a common event in NSCLC. The authors found that somatic mutations in KEAP1 were present in 50% of lung cancer cell lines and 19% of tumor samples, with all mutations occurring in highly conserved amino acid residues. These mutations likely abolish KEAP1 repressor activity. Loss of KEAP1 function leads to increased nuclear accumulation of NRF2, resulting in enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. This study demonstrates that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC, suggesting that tumor cells manipulate the NRF2 pathway to survive chemotherapy.