Serum and glucocorticoid regulated kinase 1 (SGK1) has been identified as a key regulatory protein that controls a diverse set of cellular processes including sodium (Na+) homeostasis, osmoregulation, cell survival, and cell proliferation. Two other SGK isoforms, SGK2 and SGK3, have been identified, which differ most markedly from SGK1 in their N-terminal domains. We found that SGK1 and SGK3 are potent stimulators of epithelial Na+ channel (ENaC)-dependent Na+ transport, while SGK2, which has a short N-terminus, is a weak stimulator of ENaC. Further characterization of the role of the SGK1 N-terminus revealed that its deletion does not affect in vitro kinase activity but profoundly limits the ability of SGK1 either to stimulate ENaC-dependent Na+ transport or inhibit Forkhead-dependent gene transcription. The N-terminus of SGK1, which shares sequence homology with the phosphoinositide 3-phosphate (PI(3)P) binding domain of SGK3, binds phosphoinositides in protein lipid overlay assays, interacting specifically with PI(3)P, PI(4)P, and PI(5)P, but not with PI(3,4,5)P₃. Moreover, a point mutation that reduces phosphoinositide binding to the N-terminus also reduces SGK1 effects on Na+ transport and Forkhead activity. These data suggest that the N-terminus, although not required for PI 3-kinase-dependent modulation of SGK1 catalytic activity, is required for multiple SGK1 functions, including stimulation of ENaC and inhibition of the pro-apoptotic Forkhead transcription factor. Together, these observations support the idea that the N-terminal domain acts downstream of PI 3-kinase-dependent activation to target the kinase to specific cellular compartments and/or substrates, possibly through its interactions with a subset of phosphoinositides.