Diabrotica virgifera virgifera, the western corn rootworm (WCR), is a major pest of corn in the United States. Management options include use of transgenic hybrids that expression one or more Bacillus thuringiensis (Bt) insecticidal proteins, but sustainability is threatened by field-evolved resistance. The mechanism(s) involved in D. v. virgifera cellular- or population-level responses to Bt exposures are not fully understood. We showed that the expression of stress- and cell survival genes change significantly between larvae exposed to Bt compared to non-Bt corn. Specifically, Bt intoxication involves the up-regulation of putative caspases, components of pro- and anti-apoptotic as well as endoplasmic reticulum (ER) stress-response pathways. Additionally, analysis of F2 pedigrees defined a single major QTL on chromosome 8 (Chr8) contributing to Cry3Bb1 resistance. Estimates of differentiation (FST) between resistant and susceptible populations based on whole-genome short read sequence data from pools of individuals narrowed this QTL to a Chr8 region that contains several protein coding genes (PCGs). Most significant genomic divergence was in two PCGs with putative functions in the regulation of cellular stress response and apoptosis. This region of high sequence divergence between resistant and susceptible individuals is in proximity to, but not including, two putative Bt receptors in the ATP binding cassette (ABC) transporter subfamily B (ABCB). These ABCB-encoding PCGs show no evidence of truncation or frameshift mutations. The role of the novel candidate resistance genes in the mechanism of Cry3Bb1 resistance remains unknown and will be the focus of continued research.