Young stem cells have relatively uniform epigenomes. During aging, stem cells replicate and stochastic errors in DNA methylation maintenance introduce epigenetic mosaicism. Exposures and/or chronic inflammation accelerate this process by promoting stem cell replication (e.g., for tissue repair) or by working directly on the epigenome. Continued epigenetic mosaicism results in restricted differentiation in some stem cells, leading to stem cell exhaustion and a selective growth advantage in other stem cells, which then leads to clonal expansion and local hyperproliferation. The combination of stem cell exhaustion and clonal expansion contributes to phenotypes and diseases of aging. In turn, these proliferative and restricted differentiation phenotypes promote epigenetic drift, creating a vicious cycle that exponentially increases the rate of some diseases such as cancer.