The Ah receptor (AhR) is a ligand-activated transcription factor and member of the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of chemosensors and developmental regulators. It represents a multifunctional molecular switch involved in regulation of endo- and xenobiotic metabolism, in vascular development and in dioxin-mediated toxicities. Recently, the oxidative stress-protecting Nrf2 has been shown to be a downstream target of the AhR [Miao W, Hu L, Scrivens PJ, Batist G. Transcriptional regulation of NF-E2 p45-regulated factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway. J Biol Chem 2005;280:20340-8]. This finding offers the possibility that distinct but partially overlapping AhR and Nrf2 gene batteries of Phase II xenobiotic-metabolizing enzymes can be synergistically activated by a number of phytochemicals, acting as selective or mixed activators of target genes. In addition, it is conceivable that AhR-mediated oxidative/electrophile stress may be attenuated by coupled Nrf2 activation. The commentary discusses potentials and limitations of (i) selective Nrf2 and of (ii) synergistic AhR plus Nrf2 activation by phytochemicals in efforts towards chemoprevention of cancer and degenerative diseases, and describes clinical trials providing the expectation that chemopreventive measures may favorably modulate unavoidable endo- and exogenous toxin exposures in high risk populations.