To clarify the modes of the inhibitory action of DSCG, EAA and tranilast on histamine release, the effects of these drugs were studied on anaphylactic histamine release from rat peritoneal mast cells passively sensitized with mouse anti-ovalbumin serum. DSCG had a potent and dose-dependent inhibitory effect on the release in ordinary Hanks' medium, whereas its activity was far weaker in the absence of Ca(2+). No marked differences were observed in the inhibitory activities of EAA and tranilast, irrespective of the presence or absence of extracellular Ca(2+). The inhibitory effects of the three drugs declined with prolongation of time of drug treatment before antigen challenge (development of tachyphylaxis). Once mast cells were made tachyphylactic to one of the three drugs, such cells showed markedly decreased responses to the other drugs (development of cross-tachyphylaxis). These results suggest that some common processes are involved in the mechanism of inhibition of histamine release by these drugs. It is possible that these drugs bind to the same specific sites on the surface of mast cells.