Women are relatively protected against the development and progression of glomerulosclerosis (GS) prior to menopause. However, the “female advantage” is lost in women who are either diabetic, post-menopausal or both. We showed that 17β-estradiol (E₂) was effective in prevention of diabetic GS development in part through the stabilization of podocyte cytoskeleton and a change in estrogen receptor (ER) subtype ratio. The objective of this study was to examine whether resveratrol (RSV), reported to have estrogen-like action and renoprotective activity against diabetic GS, would affect similar pathways. After in vitro treatment with RSV we found a change in the ERα and ERβ expression ratio in favor of ERβ, suppression of heat shock protein 25 (Hsp25) expression and increase in β1-integrin expression, important for maintaining podocyte cytoskeleton. We noted a reduction of insulin-like growth factor 1 receptor (IGFR1) expression, decrease in extracellular signal-regulated kinase (ERK) activation, decrease in reactive oxygen species (ROS), and decrease in cleaved-caspase 3 expression. We found an increase in [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) and an increase in matrix metalloproteinases (MMP-2 and MMP-9) activity. Using cre-loxP strategy we developed podocyte-specific ERα knockout mice to show the importance of ERβ. In isolated podocytes, we confirmed reduction of ERα expression in conjunction with a decrease in IGFR1 expression, ERK and increase of MMP-2 similar to that of our in vitro treatment with RSV. Taken together these data suggest an important role for ERβ and ER subtype ratio in podocyte stabilization. Therefore RSV or other regulators of ER pathways could offer protection against diabetic and age-related podocyte changes.