Abstract: The proliferation and multi-directional differentiation potential of mesenchymal stem cells (MSCs) enabled its wide use in the development of new therapies for bone and cartilage repair. Although preliminary work has been done to verify the gene expression profile of MSCs osteogenic and chondrogenic differentiation, it is still unclear what key factors initiate the differentiation of MSCs, resulting in its limited application in bone and cartilage tissue engineering. The epigenetic mechanism mediated by histone demethylases (lysine K-specific histone demethylases, KDMs) is the key link in regulating MSCs lineage differentiation. The lysine-specific histone demethylase (LSD) family containing Tower domain and the histone demethylase family containing Jumonji C (JmjC) domain regulate the expression of various osteogenic-related genes, including Runt-related transcription factor 2 (RUNX2), osterix (OSX), osteocalcin (OCN), to mediate MSCs osteogenic differentiation. The KDM2/4/6 subfamilies regulate the chondrogenic differentiation of MSCs through multiple pathways centered on SRY-related high-mobility-group-box gene 9 (SOX9). In addition, nanotopology, mircoRNAs, etc. regulate the expression of a variety of osteogenic and chondrogenic transcription factors through up- and down-regulation of KDMs. In summary, the role of histone demethylase in the osteogenic and chondrogenic differentiation of mesenchymal stem cells will help us better understand the pathogenesis of bone and cartilage damage diseases, and establish the foundation of future clinical applications for bone and cartilage tissue engineering.