Insecticides based on a double-stranded RNA (dsRNA) molecule activating the RNA-interference (RNAi) pathway to silence the expression of a vital gene are now commercialized in the USA as transgenic plants and sprayable pesticides. As with any other pesticide, increased adoption and continued use of these dsRNA insecticides will increase the pressure for the evolution of resistance. Implementation of insect resistance management (IRM) tools is crucial to extend the continued efficacy of dsRNA insecticides, yet information on the mechanisms and genes that may be involved in resistance to insecticidal dsRNAs is scarce. In this chapter, we critically review current knowledge of resistance to dsRNA by drawing comparisons to resistance mechanisms against alternative pesticides. Available evidence supports a preponderant role for reduced dsRNA uptake in resistance to insecticidal RNAi, independently of the dsRNA delivery method. Lack of cross-resistance to insecticidal proteins and conventional pesticides in dsRNA-resistant insects supports the combined and/or sequential use of these different modes of action to reduce selection pressure and delay resistance evolution. Future research should identify resistance genes and allow the development of DNA-based resistance screening and the improvement of insecticidal RNAi technologies.