Insecticide resistance evolution is a classic microevolutionary model typified by extreme selection pressure on natural populations. Insecticide resistance loci therefore rank as among the most likely of all insect loci to exhibit the footprints of selective sweeps. Indeed scans of the Drosophila melanogaster genome uncover loci that are the molecular targets of insecticides and genes known to detoxify insecticides. We have performed Genome wide association studies in Drosophila using insecticides with different modes of action and they confirm that major sweep loci are indeed associated with insecticide resistance. The GWAS also uncover other loci and provide us with an opportunity to search for polygenic signatures of selection. These efforts are aided by contrasting the genetic architecture of old insecticides and new insecticides that have not been around long enough to drive sweeps. Among the approaches we have explored are systems approaches that integrate polymorphism, trancriptome, and phenotypic data that reveal cohesive pathways perturbed by multiple xenobiotic compounds.