Infertility, miscarriage and aneuploid offspring increase with age in women, and meiotic dysfunction underlies reproductive aging. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay attempts at childbearing, solving this problem becomes an urgent priority. Telomeres, which consist of a (TTAGGG)n repeated sequence and associated proteins at chromosome ends, mediate aging in mitotic cells, and also may mediate the effects of aging on meiosis. Telomeres shorten both during DNA replication and from the response to oxidative DNA damage. Oocytes do not divide in adult mammals, but their precursors do replicate during fetal oogenesis. A production line exists during mammalian oogenesis- the last oocytes to exit mitosis and arrest in meiosis during fetal life are the last to ovulate in the adult, so eggs ovulated from older females have traversed more mitotic cell cycles before entering meiosis compared to eggs ovulated from younger females. Telomeres also shorten from DNA repair of oxidative damage to their guanine-rich repeats. The interval between fetal oogenesis and ovulation in the adult is exceptionally long in females attempting conception in mid life, and the inevitable exposure to reactive oxygen provides a "second hit" to telomeres. We have tested the hypothesis that telomere shortening disrupts meiosis by studying reproduction in telomerase null mice and telomere length in eggs from women undergoing in vitro fertilization (IVF). Mice normally do not exhibit age-related meiotic dysfunction, and intriguingly, mouse telomeres are much longer than human telomeres. Shortening mouse telomeres across several generations in the telomerase null state, however, recapitulates the human reproductive aging phenotype, as the mouses' telomeres approach that of older women. Moreover, oxidative stress increases with reproductive aging, leading to DNA damage preferentially at (TTAGGG)n repeats. Exposing mouse embryos to reactive oxygen species also shortens their telomeres, induces chromosome and spindle abnormalities, and promotes cell cycle arrest and apoptosis, hallmarks of reproductive aging in women. Telomeres in eggs from women who fail IVF therapy also are significantly shorter than those from women who became pregnant. Finally, if telomeres shorten with aging, how do they reset across generations? Telomerase could not play a significant role in telomere elongation during early development, because this enzyme is not active until the blastocyst stage of development, well after the stage when telomere elongation takes place. Rather, telomeres lengthen during the early development by a novel mechanism involving recombination and sister chromatid exchange. Mouse telomeres lengthen up to 10 kb during the first few cell cycles of preimplantation embryo development. Such abrupt and extensive elongation is unlikely to result from telomerase. Indeed, even embryos from telomerase null mice elongate their telomeres. Sperm also is an unlikely source of telomere repeats because telomere elongation takes place even in parthenogenetically activated eggs. DNA double strand break repair proteins appear in early embryos and blocking their action with antibodies prevents telomere elongation. CO-FISH suggests the involvement of sister chromatid exchange. Telomere dysfunction resulting from late exit during fetal oogenesis, oxidative stress, DNA damage response, and/or aberrant telomere recombination may contribute to reproductive aging-associated meiotic defects, miscarriage and infertility.