Stem cells persist for long periods in the body and experience many intrinsic and extrinsic stresses. For this reason, they present a powerful and effective DNA repair system in order to properly fix DNA damage and avoid the onset of a degenerative process, such as neoplastic transformation or aging. In this chapter, we compare the DNA repair ability of pluripotent stem cells (ESCs, iPSCs, and Muse cells) and other adult stem cells. We also describe personal investigations showing a robust and effective capacity of Muse cells in sensing and repairing DNA following chemical and physical stress. Muse cells can repair DNA through base and nucleotide excision repair mechanisms, BER and NER, respectively. Furthermore, they present a pronounced capacity in repairing double-strand breaks by the nonhomologous end joining (NHEJ) process. The studies addressing the role of DNA damage repair in the biology of stem cells are of paramount importance for comprehension of their functions and, also, for setting up effective and safe stem cell-based therapy.