Voltage-gated sodium channels are targeted by pyrethroids, which make up one of the largest classes of insecticides used globally for controlling human disease vectors and agricultural pests. Various pyrethroids can exhibit widely different toxicities on insect species. Most notably, bees are highly sensitive to most pyrethroids, but are resistant to tau-fluvalinate, a highly selective pyrethroid used to control varroa mites in beehives worldwide. However, the mechanism underlying bumblebee resistance to tau-fluvalinate remains elusive. Using mutagenesis, computer modeling of pyrethroid-receptor sites, and phylogenetic clues of sodium channel sequences, we uncovered bee-specific sodium channel residues that underlie species-specific pyrethroid selectivity. This finding could spur future development of a new generation of safer pyrethroids that selectively target pests, but not beneficial species.