Mast cell degranulation was quantitated by measuring percentage of histamine release, 45Ca2+ ion influx, or c-AMP cellular levels after stimulation with various concentrations of the sesquiterpene lactones hymenovin, helenalin, or tenulin. Hymenovin and helenalin, which contain an alpha-methylene-gamma-lactone moiety, produced extensive degranulation. Alkylation of the alpha-methylene-gamma-lactone group of these compounds with the amino acid cysteine before mast cell stimulation drastically reduced the capacity of these lactones to stimulate histamine release. Tenulin, which does not contain an alpha-methylene-gamma-lactone moiety, generally stimulated degranulation approximately equal to that of cysteine-treated hymenovin or helenalin. These data indicate that sesquiterpene lactones containing alpha-methylene-gamma-lactone are potent stimulators of mast cell degranulation. This phenomenon may have a significant role in the toxicity of some sesquiterpene lactones of poisonous plants when ingested by livestock.