Loss of function of the tumor suppressor PTEN frequently occurs in cancer. Whereas overexpression of PTEN in Drosophila causes embryonic lethality, the effect of overexpression in the mouse was unknown. Pier Paolo Pandolfi and colleagues report that increased PTEN levels unexpectedly result in viable mice that display a tumor-resistant, anti-Warburg metabolic state (Cell 149, 49–62, 2012). Transgenic Super-PTEN mice carrying the entire Pten genomic locus were constructed and found to express Pten at 1.1- to 3.5-fold higher levels than normal mice. These mice had decreased body weight and size due to decreases in cell size and number. Using chemical carcinogen–induced models of cancer, the authors found that Super-PTEN mice showed a significantly longer latency of tumor formation. Super-PTEN mice also showed an increase in energy expenditure and reduced body fat compared to wild-type mice. Cells overexpressing PTEN had decreased phosphatidylinositol 3–kinase (PI3K) activity and consumed less glucose than wild-type cells. These results indicate that PTEN overexpression leads to a reduction in PI3K-Akt signaling. Although cells from Super-PTEN mice used less glucose, they showed higher mitochondrial oxidative phosphorylation, which is consistent with an anti-Warburg state. The authors suggest that this metabolic state contributes to cancer resistance in these mice, and elevation of PTEN levels may be a potential therapeutic approach in cancer.