Most of the chemical insecticides are neurotoxic, acting on targets in the central nervous system such as the membrane ion channels (DDT, pyrethroids), the enzyme acetylcholinesterase (organophosphate, carbamate), and the receptors of neurotransmitters (avermectins, neonicotinoids). The recently introduced diamide group of insecticides target the novel ryanodine receptor in the nervous system. Since pests continue to evolve resistance to compounds currently in use, new compounds with new modes of action are needed. Natural products could be a promising source for novel pest control agents. The origin of many of the important insecticide classes is traceable to a natural source as in the case of pyrethroids, avermectins, spinosads, and neonicotinoids. Although insect control agents acting on targets other than the nervous system such as insect growth regulators (e.g., azadirachtin, JH analogues, ecdysone antagonists) have been developed, due to their lack of contact toxicity, they are not quite successful, but fi nd a place in the integrated pest management. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. Decalesides, recently discovered natural insecticides, represent a new class of plant-derived insecticides targeting the tarsal gustatory receptors. In this chapter, we focus on the toxicity and mode of action of natural insecticides.