The Keap1-Nrf2 pathway is a key regulator of cytoprotective responses to oxidative and electrophilic stress. While Nrf2 activity protects normal and premalignant tissues from cancer, it promotes tumor growth and chemoresistance in malignant cells. This review summarizes the mechanisms of Keap1-Nrf2 activation and dysregulation in cancer, and discusses how constitutive Nrf2 activation can be targeted for cancer gene therapy. The pathway involves the transcription factor Nrf2, which binds to the antioxidant response element (ARE) in target genes, and Keap1, a repressor protein that promotes Nrf2 degradation. Keap1 is a cysteine-rich protein, and modifications to its cysteine residues can lead to Nrf2 activation. Two models explain this process: the "hinge and latch" model and the Keap1-Cul3 dissociation model. Constitutive Nrf2 activation in cancer can occur through various mechanisms, including mutations in Keap1 or Nrf2, epigenetic silencing of Keap1, accumulation of disruptor proteins, and post-translational modifications of Keap1. High Nrf2 levels are associated with poor prognosis in cancer due to increased resistance to chemotherapy and radiotherapy, as well as enhanced cell proliferation. Inhibiting Nrf2 is a promising therapeutic strategy, with several approaches being explored, including the use of Nrf2 inhibitors, PI3K inhibitors, and Nrf2 siRNA. A novel approach, cancer suicide gene therapy, uses Nrf2-driven lentiviral vectors containing thymidine kinase (TK) to target cancer cells with high Nrf2 levels. When treated with the prodrug ganciclovir (GCV), these cells are effectively killed, including neighboring cells due to the bystander effect. This approach can be combined with traditional therapies to enhance treatment efficacy. Overall, while Nrf2 activity is protective in early tumorigenesis, it becomes detrimental in later stages, highlighting the need for targeted therapies to inhibit Nrf2 in cancer.The Keap1-Nrf2 pathway is a key regulator of cytoprotective responses to oxidative and electrophilic stress. While Nrf2 activity protects normal and premalignant tissues from cancer, it promotes tumor growth and chemoresistance in malignant cells. This review summarizes the mechanisms of Keap1-Nrf2 activation and dysregulation in cancer, and discusses how constitutive Nrf2 activation can be targeted for cancer gene therapy. The pathway involves the transcription factor Nrf2, which binds to the antioxidant response element (ARE) in target genes, and Keap1, a repressor protein that promotes Nrf2 degradation. Keap1 is a cysteine-rich protein, and modifications to its cysteine residues can lead to Nrf2 activation. Two models explain this process: the "hinge and latch" model and the Keap1-Cul3 dissociation model. Constitutive Nrf2 activation in cancer can occur through various mechanisms, including mutations in Keap1 or Nrf2, epigenetic silencing of Keap1, accumulation of disruptor proteins, and post-translational modifications of Keap1. High Nrf2 levels are associated with poor prognosis in cancer due to increased resistance to chemotherapy and radiotherapy, as well as enhanced cell proliferation. Inhibiting Nrf2 is a promising therapeutic strategy, with several approaches being explored, including the use of Nrf2 inhibitors, PI3K inhibitors, and Nrf2 siRNA. A novel approach, cancer suicide gene therapy, uses Nrf2-driven lentiviral vectors containing thymidine kinase (TK) to target cancer cells with high Nrf2 levels. When treated with the prodrug ganciclovir (GCV), these cells are effectively killed, including neighboring cells due to the bystander effect. This approach can be combined with traditional therapies to enhance treatment efficacy. Overall, while Nrf2 activity is protective in early tumorigenesis, it becomes detrimental in later stages, highlighting the need for targeted therapies to inhibit Nrf2 in cancer.