Insecticides are a cost-effective approach to managing disease-carrying, crop-destroying, and residential pest insects. However, current anticholinesterase insecticides are toxic to beneficial insects and vertebrates because they target the catalytic serine residue of acetylcholinesterase, a hydrolase vital to the regulation of acetylcholine in both invertebrates and vertebrates. Targeting this serine residue for more than 70 years has also contributed to current problems with insecticide resistance. This chapter presents data undergirding a mechanistically new insecticide concept that targets a cysteine residue unique in pest insect acetylcholinesterase to impart species-selective toxicity and a low propensity for resistance. These data are used to discuss how gainful deployment of the mechanism of irreversible inhibition of the acetylcholinesterase responsible for cholinergic functions in pest insects-but not in social bees and other higher social hymenopterans-may lead to cysteine-targeting anticholinesterases that are effective and environmentally safe in controlling pest insects while sparing economically important beneficial insects.