The role of $G{alpha}12;and;G{alpha}13$ in modulating the IgE receptor-mediated histamine secretion in the streptolysin-o-permeabilized human cultured mast cell was investigated. The expression of $G{alpha}12;and;G{alpha}13$ proteins were regulated during human cultured mast cell differentiation, and a significant correlation was observed between the levels of expression of $G{alpha}12;and;G{alpha}13$ proteins and IgE receptor-mediated histamine secretion capability in human cultured mast cells. Antibodies against $G{alpha}12;and;G{alpha}13$ effectively inhibited the IgE receptor-induced histamine release, and the concentration of anti-$G{alpha}12$ antibody used to inhibit histamine secretion was shown to also inhibit the IgE receptor-mediated elevation of intracellular $Ca^2+$. Therefore, the results suggest that $G{alpha}12;and;G{alpha}13$ play roles in modulating IgE receptor-activated $Ca^2+$ influx, thereby regulating histamine release in cultured human mast cells. This is the first report to show that $G{alpha}12;and;G{alpha}13$ are involved in the regulation of $Ca^2+$ mediated exocytosis in human cultured mast cells.