The susceptibility of Spodoptera frugiperda (J. E. Smith) to methomyl, diazinon, and permethrin in relation to larval development was investigated. Increased LD50s of these insecticides were associated with increasing larval instars. Sixth instars were 135-, 154-, and 236-fold more tolerant of methomyl, diazinon, and permethrin, respectively, than were 3rd instars on a per-larva basis; the tolerances became 3.1-, 3.2-, and 5.6-fold, respectively, on a body weight basis. In all instances, a larger difference in tolerance was observed between 5th- and 6th-instars than between any other two successive instars. The fact that injection of methomyl into the 5th- and 6th-instars thereby bypassing the cuticle, did not alter the tendency suggests that the large increases in tolerance in the final instars were not related to cuticular penetration. Biochemical studies revealed that increased midgut aldrin epoxidase activity was associated with increased larval instars on a protein basis. A similar pattern was also observed for the midgut glutathione S-transferase activity, whereas the midgut esterase activity appeared to be higher in younger instars. Piperonyl butoxide, the well-known inhibitor of microsomal oxidases, enhanced the toxicity of these insecticides in this insect. Changes in microsomal oxidase activity correlate well with the toxicity of these insecticides to fall armyworm larvae.