Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes and protection of tissues. Nrf2-null mice are sensitive to a wide variety of toxic electrophiles and ROS. Keap1 acts as a subunit of ubiquitin-E3 ligase and degrades Nrf2 constitutively. Keap1 also acts as a sensor for electrophilic and oxidative stresses. Covalent modifications of the cysteine residues of Keap1 abrogate the ubiquitin ligase activity and stabilize Nrf2. The two-site recognition model has been proposed for the Keap1-Nrf2 system. Disruption of the two-site recognition model explains the mechanism of nuclear accumulation of Nrf2 in a Cul3-Keap1 E3 ubiquitin ligase-dependent manner. Meanwhile, many somatic missense mutations have been identified in KEAP1 and NRF2 genes of human cancers. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2. Elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming and induction of cellular defense enzymes. The Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.