Mesenchymal stem cells(MSCs) are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus,management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su(var)3–9, enhancer-of-zeste, trithorax(SET) domain-containing family and the Jumonji C(JmjC) domain-containing family represent the major histone lysine methyltransferases(KMTs) and histone lysine demethylases(KDMs), respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containing KMTs and Jmj C domain-containing KDMs balance the osteogenic and adipogenic differentiation of MSCs. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su (var) 3-9, enhancer-of-zeste, trithorax (SET) domain- containing family and the Jumonji C (JmjC) domain-containing family represent the major histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain- containing KMTs and Jmj C domain-containing KDMs balance the osteogenic and adipogenic differentiation of MSCs.