Publisher Summary The consideration of stem cells in the context of organismal aging and longevity requires an understanding of how stem cells themselves manifest the process of aging and how those changes contribute to the phenotypes of aged tissues and organs and the entire organism. To approach this chapter examines some key distinctions and characteristics of stem cells. Then it presents general issues of aging that are relevant to stem cells. Stem cells hold the promise of cure of many human diseases, in particular degenerative diseases and diseases of aging, whether by enhancement of endogenous stem cell function or transplantation of exogenous stem cells. In the context of aging, the success of any stem-cell-based therapy will be highly dependent on the status of the niche, appreciating the likelihood that age-related changes may render the niche less able to promote optimal stem cell function. Therefore, while enhancing the functionality of endogenous stem cells or optimizing the functionality of exogenous stem cells will be important for the success of such therapy, so will any treatments that may prime or prepare the niche to support those cells optimally, particularly in the aged host. The concept that stem cells may have applications to the delay of organismal aging requires the consideration of the universality of the aging process of both the proliferative and the nonproliferative tissues and the profound influence of the systemic milieu on cells within any tissue.