A simple paralysis bioassay was used to measure the effects of sodium channel blockers and activators on third instar larvae of three strains of the house fly, Musca domestica. The pyrethroid-resistant strains kdr and super-kdr, which are thought to have rediced neural sensitivity to pyrethroids, displayed 28-fold and greater than 909-fold resistance to deltamethrin when compared to the pyrethroid-susceptible NAIDM strain. The kdr and super-kdr strains were also at least 16-fold resistant to the plant alkaloid aconitine. Previous studies on the interaction of pyrethroids and neurotoxins similar to aconitine with the sodium channel reported that these two classes of ligands bind to different receptor sites. Thus, our results demonstrate that the kdr and super-kdr resistance mechanisms modify the sensitivity of the insect nervous system to toxins which act at two distinct binding sites on the sodium channel. In contrast, the pyrethroid-resistant strains showed no cross resistance to tetrodotoxin, Leiurus quinquestriatus scorpion venon, or procaine, which suggests that the binding sites for these compounds are not altered.