The cardiac-inhibiting properties of the sesquiterpene lactone, parthenin, were examined on semiisolated heart preparations of the migratory grasshopper, Melanoplus sanguinipes. Compared with saline-treated hearts, 0.3 mM parthenin significantly increased the frequency of heartbeat. However, higher concentrations of parthenin (3.4–51.3 mM) were progressively more inhibitory and caused a cessation in heartbeat within 1 h after application.Parthenin-arrested hearts treated with reduced glutathione, DL-cystathionine, acetylcholine, or L-glutamic acid remained inactive. In contrast, L-cysteine, DL-homocysteine, or dithiothreitol (DTT) reinitiated heartbeat in parthenin-arrested hearts. When the isolated monoadduct of parthenin and cysteine was applied to heart preparations, no inhibitory effects were apparent. The inhibitory effects of parthenin could also be delayed or prevented by mixing the compound with equimolar concentrations of cysteine, homocysteine, or DTT prior to its application to the heart. Because certain thiol agents negate or neutralize the cardiac-inhibiting properties of parthenin, the findings suggest that the lethal effects of sesquiterpene lactones on insects are due, in part, to an interference with free sulphydryl groups which appear essential to normal cardiac activity.The implications of these findings are discussed in terms of the mode of action, detoxification, and importance of parthenin in plant defense.