The green peach aphid, Myzus persicae (Sulzer), elicits considerable economic damage on vegetable and ornamental crops through feeding activity and virus transmission. Acetylcholinesterase (AChE) is responsible for regulating acetylcholine (ACh) at cholinergic nerve synapses in both insects and mammals. AChE is a proven target for high efficacy, organophosphate and carbamate insecticides; however, widespread resistance of aphids to these insecticides, and poor selectivity towards humans, limits their utility in pest control programs. Within the AChE catalytic gorge, aromatic amino acid residues line and assemble important subsites for ACh and other cholinergic substrate binding. Sulfhydryl reagents inactivate AChE in aphids, but are ineffective against many other insect and mammalian AChEs. Protein homology modeling of aphid AChE suggests a species-specific cysteine (Cys286) near the peripheral site of the AChE catalytic gorge to which sulfhydryl reagents might interact. Interestingly, Cys286 is absent in mammalian AChE and, thus, may be exploited for selective anticholinesterase development. We have undertaken a systematic screen of tacrine-linked AChE inhibitors to profile the catalytic gorge of M. persicae AChE and examine the differential sensitivities of these compounds to Cys286. The implications of these structure-activity relationships to M. persicae AChE, and other insect AChEs, for insecticide design will be discussed.