Bacillus thuringiensis (Bt), a naturally occurring entomopathogenic soil bacterium, has been the active ingredient of sprayable Bt biopesticides for over a century. Insecticidal Bt Cry proteins are particularly well suited for use as plant-incorporated protectants in transgenic crops (Bt crops) due to their specificity against insect pests and safety for non-target organisms. The sustainability of these Bt products, however, has been challenged by the development of resistance in the field. RNA interference (RNAi), a species-specific control alternative that has been deregulated and commercialized in the USA and Canada, provides a new mode of action to complement the existing Bt products. Based on our preliminary research, we hypothesized that pyramiding/integrating Bt with RNAi can address/manage resistance issues related to Bt traits. To examine this overarching hypothesis, we (1) cloned and characterized a serine/threonine kinase gene (fused) of the Hedgehog (Hh) signaling pathway in the diamondback moth, Plutella xylostella (L.), a global superpest; (2) profiled Pxfused expression in Bt-resistant P. xylostella strains; and (3) investigated the involvement of Pxfused in Bt Cry1Ac resistance in P. xylostella. Pxfused expression was elevated ubiquitously in all Bt-resistant strains, and silencing of Pxfused led to larval and pupal mortality in both Cry1Ac-susceptible and -resistant strains, suggesting that Pxfused is a potential target for RNAi-based resistance management. Taken together, our results not only identify a molecular target to control a devastating lepidopteran pest, but also shed light on a novel resistance management strategy through the integration of two biotechnological techniques with distinct modes of action.