Stem cells are defined by both their ability to produce stem cells, a property known as self-renewal, and their ability to give rise to differentiated progeny. One of the hallmarks of tissue stem cell is its adoption of a non-dividing, undifferentiated state called quiescence. The ability to sustain quiescence is crucial for stem cell function in several tissues. In this review, we discuss how tissue stem cell properties are affected by the products of tumor-related genes such as ATM, PTEN and FOXO. Recent advances in stem cell research achieved using mouse genetics have provided novel evidence that numerous tumor-related genes, which are known to control genomic stability, cell proliferation and survival, are also closely associated with the regulation of tissue stem cell self-renewal. These findings support the notion that tissue stem cells and cancer cells share common properties. Further investigation of stem cell regulation by tumor-related genes may pave the way for successful stem cell-based approaches to regenerative medicine and cancer therapy.