Technical Abstract: Microarrays containing Tribolium castaneum whole-genome sequences were developed to study the transcriptome response of T. castaneum larvae to dietary protease inhibitors. In larvae fed diets containing 0.1% of the cysteine protease inhibitor E-64 alone or in combination with 5.0% of the serine protease-specific soybean trypsin inhibitor (STI), 23 and 21 genes were significantly down regulated, respectively, including protease and exopeptidase genes, and also genes involved in protein translation, energy production, cell signaling and communication, and ion transport. Four down regulated transcripts, genes encoding alkaline phosphatase, glutamate transporter, carbonate dehydratase, and perlecan, were common to larvae subjected to either E-64 or E-64 plus STI treatments. In larvae fed diets containing 5.0% STI, only two genes were significantly down regulated. Although not statistically significant, some cathepsin L and B genes were down regulated in response to E-64 or STI. In STI-treated larvae, the down regulation of serine protease genes was compensated by up regulation of alternative serine protease genes, mostly chymotrypsin. An increase in protease homologs in response to inhibitors suggests a role in protecting larvae from the negative effects of inhibitor treatments. In larvae fed combination treatments, most protease genes were down regulated and none were up regulated, supporting the hypothesis that dietary treatments containing inhibitor combinations prevent compensation responses by insects.