The Drosophila melanogaster Genetic Reference Panel, consisting of 205 inbred, sequenced lines, is a powerful tool for elucidating the genetic basis of phenotypic variation in Drosophila melanogaster through genome-wide association studies. The recent addition to of 185 sequenced transcriptomes has expanded the utility of this resource to allow the incorporation of genotype, phenotype, and gene expression into a single model. By applying this 'systems genetics' approach to insecticide resistance phenotypes we identified Cyp6g1 and Cyp12d1 as top candidate resistance loci for the insecticides azinphos-methyl and chlorantraniliprole respectively. We found, in each of these genes, that expression level was correlated with structural variation, and validated the involvement of increased expression in resistance transgenically. These findings highlight the transcriptomic and phenotypic relevance of structural variation, which is becoming more apparent as we expand beyond SNP-based association studies.