Richard Cornall and collaborators recently developed a mouse model of Ligase IV syndrome with growth retardation and immunodeficiency due to a defect in nonhomologous end-joining (NHEJ) of DNA double-strand breaks. They demonstrated age-dependent loss of hematopoietic stem cell function in these mice. Simultaneously, Irving Weissman and colleagues demonstrated a similar phenomenon in Ku80(-/-) mice defective in NHEJ and telomere maintenance, Xpd(TTD) mice defective in nucleotide excision repair, and late generation mTr(-/-) missing telomerase activity. These studies strongly support the hypothesis that genomic stress causes aging by limiting the ability of stem cells to indefinitely maintain tissue homeostasis.