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beta-Diguetoxin-Dc1a ( Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Na-v) channels (BgNa(v)1), whereas human Na-v channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNa(v)1 voltage sensors into K(v)2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNa(v)1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNa(v)1 resistance to Dc1a, we identified two residues within the BgNa(v)1 domain II S1-S2 loop that when mutated to their PaNa(v)1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Na-v channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides.