Adult stem cells must persist throughout life to ensure continuous replenishment of dead or damaged cells in various tissues of the body. While numerous studies have already begun to identify some of the factors and mechanisms that regulate long term function and survival of stem cells, there is still much to learn in this regard. A growing body of evidence suggests that various types of stem cells exist in a hypoxic microenvironment, which may be conducive to stem cell longevity. We have recently shown that the oxygen dependent transcription factor hypoxia inducible factor 1alpha (Hif1α) is essential for maintenance of functional levels of telomerase in murine embryonic stem cells (mES). Importantly, long-term proliferation of mES cells with reduced Hif1α levels led to telomere shortening and ultimately cell senescence. Studies by others over the past 10 years has also indicated that hypoxia and Hif expression are essential for self-renewal and are involved in the regulation of proliferation for some types of stem cells. We now report our view regarding the effects and mechanisms by which hypoxia may regulate the long-term maintenance of stem cell populations.