Cells are equipped with a number of transcriptional factors that safeguard against various environmental insults. Proteasomal protein degradation plays an important role in the Keap1-Nrf2 cytoprotection system, with molecular machinery similar to that for other environmental defense systems such as inflammatory and hypoxic responses. While Nrf2 protein stabilization is known to be redox-sensitive, the transcription factors NF-κB and HIF-1α for inflammatory and hypoxic responses, respectively, are also influenced by the cellular redox conditions. In this review we present the recently proposed two-site substrate recognition model of the Keap1-Nrf2 system, which regulates the cellular responses against oxidative and xenobiotic stresses. The implications of two destructive motifs in Nrf2, the ETGE and DLG motifs, which appear to function as a hinge and latch attenuating Keap1 activity in different redox states, are discussed.