By regulating glutathione S-transferase (GST) and intracellular glutathione (GSH) levels, Nrf2 controls the level of ROS in the cell induced by external stressors such as xenobiotic or electrophilic stress. In this issue of the JCI, Thimmulappa et al. show that the level of ROS regulated by Nrf2 also influences TLR4 signaling at the level of IKK activation, resulting in increased nuclear translocation of NF-κB. In addition, the authors show that IRF-3–mediated gene transcription is also regulated by Nrf2; however, at what level this occurs remains to be determined. Other potential kinase targets of ROS modification include IRAK/IRAK4 and MAPKs as well as TRAF-associated NF-κB activator–binding kinase 1 (TBK1). ARE, antioxidant response element; CBP, CREB-binding protein; HO-1, heme oxygenase I; Keap1, Kelch-like erythroid cell–derived protein with cap'n'collar homology–associated protein; Maf, mammary cell–activating factor; NQO1, quinone oxidoreductase; TIRAP, TIR-associated protein; TRAM, TRIF-related adaptor molecule.