The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2)–Keap1 signaling pathway is a critical cellular defense mechanism that protects against toxicants and carcinogens by activating a variety of cytoprotective genes. However, Nrf2 can also promote cancer progression and chemoresistance. This review provides an overview of the Nrf2–Keap1 pathway, its dual role in cancer, the molecular basis of Nrf2 activation in cancer cells, and the challenges in developing Nrf2-based drugs for chemoprevention and chemotherapy. Nrf2 is regulated by Keap1, a substrate adaptor protein for the Cullin 3 (Cul3)-dependent E3 ubiquitin ligase complex. Under basal conditions, Keap1 binds to the Nrf2 Neh2 domain and promotes its ubiquitination and proteasomal degradation. In response to oxidative stress or electrophiles, Keap1 undergoes conformational changes, disrupting its interaction with Nrf2 and leading to Nrf2 stabilization and nuclear translocation. Nrf2 then binds to antioxidant response elements (AREs) and activates the transcription of genes involved in glutathione synthesis, antioxidant proteins, drug-metabolizing enzymes, and xenobiotic transporters. While Nrf2 knockout mice show increased susceptibility to chemical-induced carcinogenesis, constitutively high levels of Nrf2 in cancer cells promote proliferation, chemoresistance, and radioresistance. The activation of Nrf2 in cancer can occur through somatic mutations in KEAP1, NRF2, or CUL3, epigenetic silencing of Keap1, aberrant accumulation of proteins that disrupt the interaction between Nrf2 and Keap1, transcriptional up-regulation of NRF2, and metabolic activation of Keap1 by fumarate. Nrf2 activators, such as sulforaphane and curcumin, have shown promise in clinical trials for chemoprevention, while Nrf2 inhibitors, such as brusatol, are being explored as potential cancer therapeutics. The dual role of Nrf2 in cancer highlights the need for selective modulation of Nrf2 activity to enhance the efficacy of cancer treatments.The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2)–Keap1 signaling pathway is a critical cellular defense mechanism that protects against toxicants and carcinogens by activating a variety of cytoprotective genes. However, Nrf2 can also promote cancer progression and chemoresistance. This review provides an overview of the Nrf2–Keap1 pathway, its dual role in cancer, the molecular basis of Nrf2 activation in cancer cells, and the challenges in developing Nrf2-based drugs for chemoprevention and chemotherapy. Nrf2 is regulated by Keap1, a substrate adaptor protein for the Cullin 3 (Cul3)-dependent E3 ubiquitin ligase complex. Under basal conditions, Keap1 binds to the Nrf2 Neh2 domain and promotes its ubiquitination and proteasomal degradation. In response to oxidative stress or electrophiles, Keap1 undergoes conformational changes, disrupting its interaction with Nrf2 and leading to Nrf2 stabilization and nuclear translocation. Nrf2 then binds to antioxidant response elements (AREs) and activates the transcription of genes involved in glutathione synthesis, antioxidant proteins, drug-metabolizing enzymes, and xenobiotic transporters. While Nrf2 knockout mice show increased susceptibility to chemical-induced carcinogenesis, constitutively high levels of Nrf2 in cancer cells promote proliferation, chemoresistance, and radioresistance. The activation of Nrf2 in cancer can occur through somatic mutations in KEAP1, NRF2, or CUL3, epigenetic silencing of Keap1, aberrant accumulation of proteins that disrupt the interaction between Nrf2 and Keap1, transcriptional up-regulation of NRF2, and metabolic activation of Keap1 by fumarate. Nrf2 activators, such as sulforaphane and curcumin, have shown promise in clinical trials for chemoprevention, while Nrf2 inhibitors, such as brusatol, are being explored as potential cancer therapeutics. The dual role of Nrf2 in cancer highlights the need for selective modulation of Nrf2 activity to enhance the efficacy of cancer treatments.