Mast cell function is regulated by glucocorticoids. The signalling of glucocorticoids includes the serum- and glucocorticoid- inducible kinase SGK1, a potent regulator of ion channel activity and hormone release. The present study explored the putative role of SGK1 in the regulation of mast cell function. Mast cells were isolated from bone marrow (BMMCs) of SGK1 knockout (sgk1-/- ) mice and their wild-type (sgk1+/+ ) littermates. Both forward and side scatter, determined by FACS analysis, were significantly smaller in sgk1-/- BMMCs. IgE-antigen (Ag) stimulation led to increased Ca2+ entry in sgk1 +/+, but not in sgk1-/- BMMCs. Ca2+ -activated K+ current, induced by IgE-Ag, was significantly higher in sgk1+/+ than in sgk1-/- BMMCs. Moreover, sgk1-/- BMMCs showed impaired antigen-IgE-induced degranulation. To explore whether the in vivo function of mast cells is affected in sgk1-/- mice, studies were performed using the trinitrochlorobenzene (TNCB)-induced contact hypersensitivity reaction. Early ear swelling after TNCB stimulation was indeed significantly reduced in sgk1-/- mice, pointing to severe impairment of mast cell function. The observations point to a critical role of SGK1 in mast cell ion channel regulation and function, and thus disclose a novel player in the regulation of allergy.