<p>The KEAP1-Cullin3-RBX1 E3 ubiquitin ligase complex functions as the central molecular gatekeeper of cellular redox homeostasis by tightly regulating the degradation of nuclear factor erythroid 2–related factor 2, a master transcriptional regulator of antioxidant and cytoprotective genes. Under basal physiological conditions, this complex ensures a finely tuned, transient activation of Nrf2, thereby preventing unnecessary antioxidant gene expression while maintaining readiness against oxidative insults. In response to oxidative or electrophilic stress, conformational modifications in KEAP1 cysteine residues impair Nrf2 ubiquitination, enabling its nuclear translocation and activation of a wide range of target genes involved in detoxification, metabolic regulation, and cellular repair. While transient activation of Nrf2 is protective against acute stress and chronic degenerative disorders, persistent activation—often due to mutations in KEAP1 or <i>NFE2L2</i>—can drive tumorigenesis, chemoresistance, metabolic reprogramming, and immune evasion. This review summarizes the structural and mechanistic underpinnings of the KEAP1-Cullin3-RBX1 complex, explores the dual context-dependent roles of Nrf2 in health and disease, and highlights current therapeutic strategies aimed at modulating this pathway. However, despite significant advances, limitations remain in fully elucidating the context-specific consequences of Nrf2 activation, the heterogeneity of its downstream effects across cancer types, and the long-term safety of pharmacological Nrf2 modulators. Further research is therefore essential to define biomarkers of Nrf2 dependency, optimize therapeutic windows, and integrate pathway modulation into precision medicine frameworks. A deeper understanding of this regulatory axis may ultimately transform Nrf2 from a compelling molecular target into a cornerstone of redox-based precision therapeutics.</p>