Stem cell function declines with age in both humans and mice. It has been hypothesized that aging of stem cells is the underlying cause of impaired tissue homeostasis as well as cancer in aged individuals, which might ultimately limit the lifespan. In 1978, Schofield proposed the 'niche' hypothesis to describe the physiologically limited microenvironment that supports stem cells. This hypothesis has been confirmed in multiple stem cell systems from distinct organisms over the last decade and is currently an active field of research in stem cell biology. In recent years the effect of aging of the niche on altered phenotypes associated with aged stem cells has been more and more appreciated. One central question in stem cell aging research is consequently the identification of the contribution of stem cell intrinsic versus extrinsic factors (including the niche and/or systemic factors) to stem cell aging, which is critically important with respect to therapeutic interventions in light of reversion/rejuvenation. The following chapter summarizes presentations from the 3rd Else Kroner-Fresenius Symposium on Molecular Mechanisms of Stem Cell Aging that focused primarily on elucidating alterations of stem cell-niche interactions, age-associated leukemia, and systemic influences on stem cell aging, both in Drosophila and mice, provided by Drs. Xie, Yamashita, Jones, DeGregori, and Geiger. Copyright (C) 2012 S. Karger AG, Basel