The present study demonstrates that the serum- and glucocorticoid-inducible kinase 1 (SGK1) controls migration of bone marrow-derived mast cells (BMMCs). Wild-type BMMCs migrate after stimulation with dinitrophenylated human serum albumin or thapsigargin whereas both stimuli did not induce migration of sgk1^-/- BMMCs. Mast cell migration requires store-operated Ca²⁺ entry (SOCE) through the Ca²⁺ channels, which in BMMCs consist of the pore-forming subunit Orai1 and the Ca²⁺-sensing subunit STIM1. Accordingly, blocking SOCE by 2-APB abrogated migration of sgk1^+/+ BMMCs. SOCE induced by the inhibition of endosomal Ca²⁺ ATPase with thapsigargin (1 mM) was significantly lower in sgk1^-/-than in sgk1^+/+ BMMCs. Two mechanisms of SGK1-mediated regulation of SOCE were discovered. First, transcript levels of Orai1 and STIM1 were diminished in sgk1^-/-BMMCs. Transfection with active NF-kB subunit p65 strongly increased Orai1 and STIM1 transcript levels in sgk1^-/-and sgk1^+/+ BMMCs. Genomic regulation of Orai1/STIM1 by SGK1-dependent NF-kB signalling was confirmed in HEK293 cells in which Orai1 and STIM1 transcript levels were enhanced upon transfection with active ^S422DSGK1 but not inactive ^K127NSGK1 and not in ^S422DSGK1-transfected cells treated with the NF-kB inhibitor Wogonin (100 mM). Secondly, SGK1 enhanced the abundance of Orai1 in the plasma membrane through phosphorylation and inactivation of the ubiquitin ligase Nedd4-2, which ubiquitinates and initiates the degradation of Orai1. In Orai1/STIM1-expressing HEK293 cells coexpression of Nedd4-2 down-regulated Orai1 protein abundance and SOCE, both effects reversed by expression of ^S422DSGK1. SGK1 is therefore a novel key player in the regulation of SOCE and SOCE-dependent functions, such as mast cell migration.