In this study, we uncovered a novel mechanism by which human embryonic stem cells and mouse epiblast stem cells retain their pluripotency, or ability to differentiate into virtually any kind of cell. We found that Wnt/beta-catenin signaling pathway—a group of molecules that work together to control various cell functions, can prompt human embryonic stem cells and mouse epiblast stem cells to either self-renew or differentiate. When the protein beta-catenin remains within the cell cytoplasm but outside of the nucleus, the stem cell continues to self-renew. When beta-catenin moves into a stem cell’s nucleus, differentiation begins. Our study will advance our efforts to better control stem cell fate, which is critical to the future of regenerative medicine.