Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma (SCC) cells. In this study, we show that oral administration of RES to highly tumor-susceptible p53+/-SKH-1 mice markedly delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Transforming growth factor-Β2 (TGF-Β2) was predominantly overexpressed in UV-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to the inhibition of TGF-Β2 expression, RES increased the level of epithelial cadherin. This RES-mediated TGF-Β2 downregulation led to the inhibition of both TGF-Β2/Smad- dependent and-independent pathways, and suppressed the invasiveness of A431 cells. Addition of TGF-Β2, but not TGF-Β1, rescued the RES-mediated downregulation of p-extracellular signal-regulated kinases 1/2, p-Smad3, and α-smooth muscle actin. The protein kinase B (Akt) substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF-Β2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF-Β2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UV-induced malignant tumor progression in p53 +/-SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-Β2. © 2011 The Society for Investigative Dermatology.