While protective in normal cells, constitutive NRF2 activation driven by loss-of-function mutations in <i>KEAP1</i>, gain-of-function mutations in <i>NFE2L2</i>, or non-mutational mechanisms is common in cancer, occurring in approximately 20%-30% of non-small cell lung cancers and at significant frequencies across multiple tumor types. The gene discussed is NFE2L2; the disease is cancer.