When histamine releasers such as sinomenine, compound 48/80, PVP and Tween 20 were given intravenously by a series of injections in the scheduled doses increasing very gradually from a minute amount, dogs were made resistant against the shock doses of respective releaser while there were no significant changes both in the arterial blood pressure and in the plasma histamine level, i.e. no evidence of histamine release during the procedure. These resistant dogs responded well to intravenous injection of histamine as in the normal dog. The dogs made resistant to compound 48/80 were found also to be resistant to sinomenine and vice versa (cross tolerance). A cross-tolerance was also noticed between PVP-and Tween 20-resistant dogs. However, the dogs resistant to sinomenine and to 48/80 reacted to both PVP and Tween 20 as normal dogs. And the same was held in the converse. Similar findings were also seen in the skin reaction and in the histamine release from the chopped skin by these histamine releasers. In neither of these two groups of the resistant dogs, anaphylactic shock and peptone shock were inhibited. The mechanisms leading, to a resistance against a certain releaser by repeating the injections of it were discussed and it was assumed that a family of histamine releasers of different chemical structures possibly share a common site of action on the surface of mast cell membrane.