Mast cell degranulation is a dynamic, highly organized process involving numerous signaling molecules and enzymes. Although the molecular mechanisms underlying antigen‐mediated mast cell degranulation have been studied intensively, little is known about the transcriptional control of this process. Here, we show that the hematopoietic transcription factors GATA1 and GATA2 are involved in mast cell degranulation through the control of phospholipase C‐γ1 (PLC‐γ1) expression. Knockdown of GATA1 and/or GATA2 by specific siRNA significantly reduced antigen‐induced degranulation and Ca2+ mobilization in the rat basophilic leukemia cell line RBL‐2H3. RT‐PCR analyses showed that PLC‐γ1 expression was significantly decreased by this GATA factor repression. Other GATA factor targets, such as the previously reported α and β subunits of the high‐affinity IgE receptor (FcεRI), were unaffected. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that GATA factors directly activate PLC‐γ1 gene transcription through a conserved GATA‐binding motif that resides in the 5′‐upstream sequence. Furthermore, we show evidence that the PLC‐γ1 expression is regulated by GATA2 in mast cells derived from mouse bone marrow. These data indicate that PLC‐γ1 is a target gene of GATA factors in mast cells and provide evidence that GATA1 and GATA2 control antigen‐mediated mast cell degranulation by regulating the expression of PLC‐γ1.