Drosophila sechellia is a species of fruit fly endemic to the Seychelles islands. Unlike its generalist sister species (D. simulans, D. mauritiana, and D. melanogaster), D. sechellia has evolved to specialize on a single host plant, Morinda citrifolia. Specialization on M. citrifolia is interesting because the fruit of the plant contains secondary defense compounds, primarily octanoic acid (OA), that are lethal to all other Drosophila species. Although ecological and behavioral adaptations to this toxic fruit are known, the genetic bases for evolutionary changes in OA resistance are not. Prior work showed that a genomic region on chromosome 3R containing 18 genes has the greatest contribution to differences in OA resistance between D. sechellia and D. simulans. To determine which gene(s) in this region might be involved in the evolutionary change in OA resistance, we knocked-down expression of each gene in this genomic region in D. melanogaster with RNA interference (RNAi) (i) ubiquitously throughout development, (ii) during only the adult stage, and (iii) within specific tissues. We identified three neighboring genes that decreased OA resistance when ubiquitously knocked-down. Tissue specific RNAi, however, showed that decreasing expression of two of these genes specifically in the fat body and salivary glands increases OA resistance demonstrating how specific changes in gene expression can differ from a global change in expression levels. Both genes have derived expression levels in D. sechellia and no changes in protein sequence suggesting differences in cis-regulation contribute to host specialization in D. sechellia.