Mammalian aging is associated with reduced tissue regeneration, increased degenerative disease, and cancer. Because stem cells regenerate many adult tissues and contribute to the development of cancer by accumulating mutations, age-related changes in stem cells likely contribute to age-related morbidity. Consistent with this, stem cell function declines with age in numerous tissues as a result of gate-keeping tumor suppressor expression, DNA damage, changes in cellular physiology, and environmental changes in tissues. It remains unknown whether declines in stem cell function during aging influence organismal longevity. However, mechanisms that influence longevity also modulate age-related morbidity, partly through effects on stem cells.