Mouse embryonic stem (ES) cells in culture defy cellular senescence and undergo more than 250 doublings without undergoing crisis or transformation. They tend to maintain a normal karyotype and high genome integrity. Mouse ES cells are thus often considered “immortal” cells. We have recently found that Zscan4, which was originally identified for its 2-cell embryo-specific expression, plays a critical role in the maintenance of genome stability and telomerase-independent telomere elongation. The implication of this finding to stem cell biology and aging research will be discussed.