Neuropathy target esterase (NTE) is a membrane-bound protein with high esterase catalytic activity. The physiological function of the protein is not known and the catalytic activity is not essential to health of nerve axons. Nevertheless there is overwhelming evidence that modification of the structure of NTE by covalent binding of some organophosphorus esters initiates an irreversible polyneuropathy: this event can be monitored. The experimental evidence for this conclusion is reviewed and some conceptual objections are resolved. Studies of NTE have generated successful predictions concerning (1) prophylaxis; (2) structure-activity relationships including stereospecificity; (3) the effects of prolonged low-level administration of neurotoxicants; and (4) extrapolations from (a) NTE responses seen after low doses to enzyme and clinical effects seen after high doses, (b) from in vitro to in vivo, and (c) from hen to human responses. The relationship of initiation on NTE to subsequent events in development of neuropathy is considered. Purification of NTE is reaching the point where antibodies may be obtained for neurobiological study. No single rigid protocol can be devised for incorporation of NTE assays into toxicological evaluations. A proposed two-stage procedure requires interpretation of Stage 1 to influence the design of Stage 2.