The Nrf2-Keap1 signaling pathway plays a critical role in cellular defense and survival, protecting cells from toxicants and carcinogens by upregulating cytoprotective genes. However, its role in cancer is dual: it can protect normal and cancer cells from chemotherapy and radiotherapy, promoting cancer progression. Nrf2 is often aberrantly accumulated in cancer, correlating with poor prognosis and drug resistance. This review discusses the Nrf2-Keap1 pathway, its dual role in cancer, molecular mechanisms of Nrf2 activation, and challenges in developing Nrf2-targeted drugs for cancer prevention and treatment. Nrf2 is a transcription factor belonging to the Cap 'N' Collar (CNC) family, with a conserved basic leucine zipper (bZIP) structure. It activates the antioxidant response by inducing genes that combat oxidative stress and xenobiotics. Nrf2 is regulated by Keap1, a substrate adaptor for the Cul3-dependent E3 ubiquitin ligase complex. Under basal conditions, Keap1 binds to Nrf2, promoting its ubiquitination and degradation. Oxidative stress or electrophiles can modify Keap1, leading to Nrf2 stabilization and nuclear translocation, where it dimerizes with Maf proteins and binds to AREs, activating cytoprotective genes. Nrf2 has tumor suppressor functions, protecting against chemical carcinogens in mice. However, its constitutive activation in cancer cells enhances survival and progression. Nrf2 promotes cancer cell proliferation by maintaining redox balance and generating antioxidants. It also contributes to chemoresistance and radioresistance by enhancing drug efflux and reducing oxidative stress. Nrf2 is constitutively elevated in various cancers, correlating with poor prognosis. Mechanisms of Nrf2 activation in cancer include somatic mutations in KEAP1, NRF2, or CUL3; epigenetic silencing of Keap1; aberrant accumulation of proteins disrupting Nrf2-Keap1 interaction; oncogene-dependent signaling; and metabolic intermediates modifying Keap1. Nrf2 activators include natural compounds like sulforaphane, curcumin, and synthetic agents like oltipraz and dimethyl fumarate. Nrf2 inhibitors include brusatol and all-trans retinoic acid, which suppress Nrf2 activity. The dual role of Nrf2 in cancer highlights the need for targeted therapies that modulate Nrf2 to enhance chemoprevention and chemotherapy. Future research aims to improve the specificity of Nrf2-based therapies, leveraging structural insights and miRNA regulation to control Nrf2 activity. Despite challenges, Nrf2 modulation offers promising avenues for cancer treatment.The Nrf2-Keap1 signaling pathway plays a critical role in cellular defense and survival, protecting cells from toxicants and carcinogens by upregulating cytoprotective genes. However, its role in cancer is dual: it can protect normal and cancer cells from chemotherapy and radiotherapy, promoting cancer progression. Nrf2 is often aberrantly accumulated in cancer, correlating with poor prognosis and drug resistance. This review discusses the Nrf2-Keap1 pathway, its dual role in cancer, molecular mechanisms of Nrf2 activation, and challenges in developing Nrf2-targeted drugs for cancer prevention and treatment. Nrf2 is a transcription factor belonging to the Cap 'N' Collar (CNC) family, with a conserved basic leucine zipper (bZIP) structure. It activates the antioxidant response by inducing genes that combat oxidative stress and xenobiotics. Nrf2 is regulated by Keap1, a substrate adaptor for the Cul3-dependent E3 ubiquitin ligase complex. Under basal conditions, Keap1 binds to Nrf2, promoting its ubiquitination and degradation. Oxidative stress or electrophiles can modify Keap1, leading to Nrf2 stabilization and nuclear translocation, where it dimerizes with Maf proteins and binds to AREs, activating cytoprotective genes. Nrf2 has tumor suppressor functions, protecting against chemical carcinogens in mice. However, its constitutive activation in cancer cells enhances survival and progression. Nrf2 promotes cancer cell proliferation by maintaining redox balance and generating antioxidants. It also contributes to chemoresistance and radioresistance by enhancing drug efflux and reducing oxidative stress. Nrf2 is constitutively elevated in various cancers, correlating with poor prognosis. Mechanisms of Nrf2 activation in cancer include somatic mutations in KEAP1, NRF2, or CUL3; epigenetic silencing of Keap1; aberrant accumulation of proteins disrupting Nrf2-Keap1 interaction; oncogene-dependent signaling; and metabolic intermediates modifying Keap1. Nrf2 activators include natural compounds like sulforaphane, curcumin, and synthetic agents like oltipraz and dimethyl fumarate. Nrf2 inhibitors include brusatol and all-trans retinoic acid, which suppress Nrf2 activity. The dual role of Nrf2 in cancer highlights the need for targeted therapies that modulate Nrf2 to enhance chemoprevention and chemotherapy. Future research aims to improve the specificity of Nrf2-based therapies, leveraging structural insights and miRNA regulation to control Nrf2 activity. Despite challenges, Nrf2 modulation offers promising avenues for cancer treatment.