||Xenobiotic compounds, such as pollutants, pesticides and other foreign chemicals, represent a constant threat to the survival of all organisms. To overcome this threat, animals mount an elaborate transcriptional response, regulating a battery of genes that provide detoxification and protective functions. Proper regulation of this response is crucial as misregulation of detoxification gene expression leads to serious consequences, including resistance to cancer chemotherapy. Similarly, insects overexpressing detoxifying genes develop resistance to pesticides, which has important implications for agricultural crop protection and the control of vector borne diseases. Although much is known about how transcription factors control xenobiotic detoxification in vertebrates, we still have a limited understanding about how this response is regulated in insects. In this thesis, I describe the use of the fruit fly, Drosophila, as a simple system to define the molecular mechanisms of xenobiotic detoxification. Exposure of flies to diverse chemicals, including phenobarbital, caffeine and chlorpromazine, triggers a rapid and coordinated change in the expression of a large battery of detoxification genes, with similar time course and dose-response profiles, suggesting that a common set of transacting factors regulate this process. I showed that the CncC/Keap1 pathway plays a central role in regulating xenobiotic responses in Drosophila. Consistent with this role of CncC in detoxification gene expression, constitutive activation of the pathway provides protection against the pesticide malathion. Further, I explored the role of the CncC/Keap1 iv pathway in acquired insecticide resistance. Several field-derived and laboratory-selected insecticide resistant strains of Drosophila overexpress a number of detoxifying genes. However, the mechanisms underlying this coordinate transcriptional response remain unknown. I showed that the CncC/Keap1 pathway is constitutively active in the two DDT resistant strains of Drosophila that are currently available. I further showed that the mutation that leads to constitutive activation of the pathway is located on the third chromosome in both of these strains. Taken together, these studies identify the evolutionarily conserved CncC/Keap1 pathway as a key regulator of xenobiotic detoxification in Drosophila, define activation of this pathway as a potential mechanism for the acquisition of metabolic insecticide resistance, and provide new directions for the control of insect populations.