Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual development of cardiac failure. Compelling evidence points to a critical role of enhanced cardiac Na⁺/H⁺ exchanger (NHE1) activity in the underlying pathophysiology. The signaling triggering up-regulation of NHE1 remained, however, ill defined. The present study explored the involvement of the serum- and glucocorticoid-inducible kinase Sgk1 in cardiac remodeling due to transverse aortic constriction (TAC). To this end, experiments were performed in gene targeted mice lacking functional Sgk1 (sgk1^-/-) and their wild type controls (sgk1^+/+). Transcript levels have been determined by RT-PCR, cytosolic pH (pHi) utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, Na⁺/H⁺ exchanger activity by the Na⁺ dependent realkalinization after an ammonium pulse, ejection fraction (%) utilizing cardiac cine magnetic resonance imaging and cardiac glucose uptake by PET imaging. As a result, TAC increased the mRNA expression of Sgk1 in sgk1^+/+ mice, paralleled by an increase in Nhe1 transcript levels as well as Na⁺/H⁺ exchanger activity, all effects virtually abrogated in sgk1^-/- mice. In sgk1^+/+mice, TAC induced a decrease in Pgc1a mRNA expression, while Spp1 mRNA expression was increased, both effects diminished in the sgk1^-/- mice. TAC was followed by a significant increase of heart and lung weight in sgk1^+/+ mice, an effect significantly blunted in sgk1^-/- mice. TAC increased the transcript levels of Anp and Bnp, effects again significantly blunted in sgk1^-/- mice. TAC increased transcript levels of Collagen I and III as well as Ctgf mRNA and CTGF protein abundance, effects significantly blunted in sgk1^-/- mice. TAC further decreased the ejection fraction in sgk1^+/+ mice, an effect again attenuated in sgk1^-/- mice. Also, cardiac FDG-Glucose uptake after TAC was increased to a larger extent in sgk1^+/+ mice than sgk1^-/- mice. These observations point to an important role for SGK1 in cardiac remodeling and development of heart failure following an excessive work load.