Mast cells, perhaps best known by their ability to trigger allergic reactions after stimulation through the FcϵRI, express the unusual phosphatidylinositol 3-kinase (PI3K)-dependent, Rac-binding protein SWAP-70. Here, we show that the IgE-mediated passive cutaneous and the systemic anaphylactic responses are strongly reduced in SWAP-70–/– mice. Cultured SWAP-70–/– immature bone marrow mast cells (BMMC) are also impaired in FcϵRI-mediated degranulation, which can be restored by expression of exogenous wild-type SWAP-70, but less so if a phosphatidylinositol trisphosphate (PIP3) binding mutant is expressed. SWAP-70 itself supports inositol-3-phosphate and PIP3 production, the latter indicating a potential feedback from SWAP-70 towards PI3K. FcϵRI-stimulated transcription and release of cytokines is controlled by SWAP-70. Key FcϵRI signal transduction events like activation of LAT by phosphorylation, activation of Akt/PKB and of p38 MAP kinase are reduced in SWAP-70–/– BMMC, but ERK is strongly hyperactivated. Some requirements for SWAP-70 were apparent only under limited-strength signaling conditions. We suggest that SWAP-70 defines a new element of efficient mast cell activation upon FcϵRI signaling, important for the control of mast cell-dependent anaphylaxis.