Cytochrome P450 monooxygenases (P450s) are known to play a central role in the adaptive response of insects and other animals to chemicals in the environment. Drosophila spp. P450s are known to be regulated by Cap ‘n’ collar isoform C (CnCC) and/ Spineless (ss) which are orthologs to Nuclear factor erythroid-2 factor 2 (Nrf2)/Aryl hydrocarbon receptor (AhR) in higher mammals. However, the mechanism underpinning this regulation in insects including fruit fly, Drosophila melanogaster is poorly understood. Understanding the constitutive and inducible patterns of expression requires knowledge about the signalling pathways that control insect P450 expression, which is still lacking for most identified insect P450s. D. melanogaster, because of its longstanding use as a genetic model insect, is a powerful tool for identifying possible regulatory mechanisms and for following expression through to function. Here, we describe the roles played by the cis-acting elements and the Transcription Factors (TFIF) mechanisms involved in the regulation of cytochrome P450 genes in D. melanogaster in response to xenobiotic compounds. These cis-acting elements include; promoters, enhancers, repressors, silencers and insulators. The regulatory mechanisms involved in the regulation of the P450s by the spineless (ss)/tango (Tgo) and CnCC/dKeap1 (Drosophila Kelch-like ECH-associated protein 1) signalling pathways in insecticide resistance were also extensively discussed. This review increases our understanding of the regulatory mechanisms involved in the insecticide metabolism in Drosophila melanogaster.