Endogenous tumor suppression provides a barrier against oncogenesis, but the molecular requirements of this process are not well understood. Here, we show that the dual specificity phosphatase PTEN, a gene almost universally altered in human tumors, silences the expression of survivin, an essential regulator of cell division and apoptosis in cancer. This pathway is independent of p53, involves active repression of survivin gene transcription, and is mediated by direct occupancy of the survivin promoter by FOXO1 and FOXO3a factors. Conditional deletion of PTEN in the mouse prostate causes deregulated induction of survivin before full-blown transformation in vivo, whereas expression of survivin and PTEN is inversely correlated in cancer patients. Therefore, silencing the survivin gene is an essential requirement of endogenous PTEN tumor suppression.