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Temporomandibular joint (TMJ) osteoarthritis is a degenerative disease, characterized by gradual cartilage degradation, bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical therapy have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In last years, stem cell-based therapy has collected much attention as a possible approach toward tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will describe the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ, particularly focusing on the MSC-based therapy and tissue engineering., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)