Emerging evidence indicates that epigenetic regulators are critically required for the maintenance of tissue-specific stem cells and that the epigenetic marks are altered in stem cells during physiological aging. Intriguingly, aging-associated stem cell functional decline can be reversed by manipulating epigenetic factors that become dysregulated during aging. These observations lend support to the stem cell theory of aging, which postulates that aging is the result of the inability of tissue-specific stem cells to replenish the tissues with functional differentiated cells that maintain the function of a tissue, and open a new era of research on the epigenetics of stem cell aging that may represent therapeutic potential. Recent advances in single cell technologies are revolutionizing our mechanistic understanding of rare populations of cells, such as stem cells, and offer an unprecedented opportunity to address this challenge.