Mesenchymal stem cells ( MSCs) are adult stem cells with self-replication and multi-directional differentiation abilities. MSCs can differentiate into various human tissues such as bone, cartilage, and muscle, and thus have broad clinical application prospects in the endogenous repair of human tissues. However, increased cell replication and aging mean that MSCs inevitably face the problem of senescence, which affects and limits their clinical application. To allow MSCs to be applied more effectively in basic and clinical research, it is necessary to study the mechanisms responsible for their senescence and develop strategies to prevent its occurrence. This report highlights the role of epigenetics in MSC senescence.