Ginsenoside-Rg1, the most prevalent active constituent of ginseng, is a potent proangiogenic factor of vascular endothelial cells. This suggests that Rg1 may be a new modality for angiotherapy. Rg1 can activate the glucocorticoid receptor (GR). However, the regulatory steps downstream from GR that promote Rg1-induced angiogenesis have not been elucidated. Here we showed for the first time that Rg1 was a potent stimulator of vascular endothelial growth factor (VEGF) expression in human umbilical vein endothelial cells, and importantly this induction was mediated through a phosphatidylinositol 3-kinase (PI3K)/Akt and beta-catenin/T-cell factor-dependent pathway via the GR. Rg1 stimulation resulted in an increase in the level of beta-catenin, culminating its nuclear accumulation, and subsequent activation of VEGF expression. Transfection of a stable form of beta-catenin (S37A) or the use of a glycogen synthase kinase 3beta inhibitor to stabilize beta-catenin induced VEGF synthesis, whereas small interfering RNA-mediated down-regulation of beta-catenin did not, confirming that the effect was beta-catenin-specific. Using a luciferase reporter gene assay, we observed that Rg1 increased T-cell factor/lymphoid enhancer factor transcriptional activity. These events were mediated via a PI3K-dependent phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase 3beta. In addition, the GR antagonist RU486 was able to inhibit Rg1-induced PI3K/Akt and beta-catenin activation. These findings provide new insights into the mechanism responsible for Rg1 functions.