Xenobiotic compounds pose a constant threat to the survival of all organisms and to overcome this, animals mount an elaborate transcriptional response, regulating a battery of enzymes that detoxify these compounds. Several transcription factors have been identified in vertebrates that regulate this response. In contrast, little is known about this pathway in insects. We show that the Drosophila Nrf2 ortholog, CncC, is a central regulator of xenobiotic detoxification responses. A binding site for CncC and its heterodimer partner Maf is sufficient and necessary for robust transcriptional responses to three xenobiotic compounds, phenobarbital (PB), chlorpromazine, and caffeine. Genetic manipulations that alter the levels of CncC, or its negative regulator Keap1, lead to predictable changes in xenobiotic‐inducible gene expression. Transcriptional profiling studies reveal that more than half of the genes regulated by PB are also controlled by CncC. Consistent with these effects on detoxification gene expression, activation of the CncC/Keap1 pathway in Drosophila is sufficient to confer resistance to the pesticide malathion. Further, in the two pesticide‐resistant strains of Drosophila , the pathway is constitutively active, leading to overexpression of several detoxification genes. Our current efforts are aimed at identifying the mutations that constitutively activate the pathway in these strains.