Naturally derived volatile insecticides from the heterobicyclic and formate ester classes were investigated using a combination of volatility and synergist bioassays. In these studies, Drosophila melanogaster (Meigen) was used as a model for other medically important dipterans. In addition to a susceptible strain (Canton-S), three mutant strains were tested that included a strain resistant by P450-based metabolism (Hikone-R) and two resistant neurological mutant strains; one voltage-gated sodium channel mutant (para^ts-1) and one GABA-gated chloride channel mutant (Rdl). In general, the 11 tested insecticides displayed a diversity of toxicity, metabolism, and resistance characteristics that correlate with their structural diversity. Several important trends were revealed by these studies, including hydrolase- and cytochrome P450 (P450)-based activation, P450-based resistance, distinct patterns of neurological activity, and negative cross-resistance with established insecticides. These findings provide important insight into the metabolism and modes of action for the volatile insecticides. These findings also suggest potential approaches for insecticide deployment in integrated vector management and resistance management programs.