PI3K-Akt-FoxO pathway is intimately linked to aging and cancer – complex biological processes brought about via the opposing actions of this pathway on degeneration on the one hand versus unlimited growth and survival potential on the other. A wealth of experimental evidence points to the importance of this signaling axis in control of stem/precursor cells in nearly all tissue that serve to maintain organ function throughout lifetime. The loss of correct cell fate decision program and/or self-renewal capacity of tissue stem cells may underlie certain degenerative diseases and constitute a part of cellular transformation. Thus identifying and understanding the genes and pathways governing tissue stem cell reserves and their restorative functions would be fundamentally important. We and others have demonstrated the lack of FoxO function elicits precocious decline in stem cells as a function of age (Tothova et al. 2007, Paik et al. 2009). Despite comprehensive genetic studies have been conducted, major questions remain as to output of PI3K-Akt-FoxO axis that regulates stem cell homeostasis. In order to address this question we combine both in vivo and in vitro systems and use them to delineate intrinsic and extrinsic control mechanism of stem cell fate decision process. We hope to& apply those findings toward invention of cellular therapeutics for degenerative diseases and better understanding of cancer.