Insulin stimulates cellular K⁺ uptake leading to hypokalemia. Cellular K⁺ uptake is accomplished by parallel stimulation of Na⁺/H⁺ exchange, Na⁺,K⁺,2Cl⁻ co-transport, and Na⁺/K⁺ ATPase and leads to cell swelling, a prerequisite for several metabolic effects of the hormone. Little is known about underlying signaling. Insulin is known to activate the serum and glucocorticoid-inducible kinase SGK1, which in turn enhances the activity of all three transport proteins. The present study thus explored the contribution of SGK1 to insulin-induced hypokalemia. To this end, gene-targeted mice lacking SGK1 (sgk1 ^−/− ) and their wild-type littermates (sgk1 ^+/+ ) have been infused with insulin (2 mU kg⁻¹ min⁻¹) and glucose at rates leaving the plasma glucose concentration constant. Moreover, isolated liver perfusion experiments have been performed to determine stimulation of cellular K⁺ uptake by insulin (100 nM). As a result, combined glucose and insulin infusion significantly decreased plasma K⁺ concentration despite a significant decrease of urinary K⁺ excretion in sgk1 ^+/+ but not in sgk1 ^−/− mice. Accordingly, the plasma K⁺ concentration was within 60 min significantly lower in sgk1 ^+/+ than in sgk1 ^−/− mice. In isolated liver perfusion experiments, cellular K⁺ uptake was stimulated by insulin (100 nM), an effect blunted by 72% in sgk1 ^−/− mice as compared to sgk1 ^+/+ mice. Accordingly, insulin-induced cell hydration was 63% lower in sgk1 ^−/− mice than in sgk1 ^+/+ mice. Moreover, volume regulatory K⁺ release was 31% smaller in sgk1 ^−/− mice than in sgk1 ^+/+ mice. In conclusion, the serum and glucocorticoid-inducible kinase SGK1 participates in the signaling mediating the hypokalemic effect of insulin.