Mesenchymal stem/stromal cells (MSCs) have emerged as promising candidates for periodontal regeneration, offering potential solutions to the limitations of traditional guided tissue regeneration (GTR) techniques. While GTR has shown effectiveness in reducing pocket depth and improving attachment gain, its narrow surgical indications and complications pose challenges. MSCs, with their capacity for self-renewal, multipotency, immunomodulation, and tissue regeneration, are considered valuable for regenerative medicine. MSCs can be derived from various sources, including non-odontogenic tissues like bone marrow, adipose tissue, and umbilical cord, as well as odontogenic tissues such as dental pulp, periodontal ligament, and apical papilla. Additionally, MSCs can be generated from induced pluripotent stem cells (iPSCs), which offer the advantage of unlimited expansion and reduced heterogeneity. However, iPSC-derived MSCs (iMSCs) require careful differentiation to avoid tumorigenic risks. MSCs are typically transplanted using scaffolds or scaffold-free methods, with biocompatible materials like collagen, chitosan, and bioceramics being commonly used. Scaffold-free techniques, such as cell sheet technology and clumps of MSCs/ECM complexes (C-MSCs), have shown promise in promoting periodontal tissue regeneration. 3D printing technologies are also being explored to create customized scaffolds for complex periodontal defects. Despite these advancements, challenges remain, including the need for standardized protocols, long-term storage of MSCs, and ensuring consistent therapeutic efficacy. MSCs also face immunological challenges, with allogeneic MSCs potentially triggering immune responses. However, iMSCs may offer improved immune compatibility. While preclinical studies demonstrate the potential of MSCs in periodontal regeneration, clinical trials are limited, and the long-term safety and effectiveness of MSC-based therapies remain to be fully established. Further research is needed to optimize MSC isolation, differentiation, and delivery methods, as well as to address the heterogeneity of MSC populations and their immune interactions. The future of periodontal regeneration may rely on a combination of MSC-based therapies, advanced scaffolding, and 3D printing technologies to achieve successful tissue repair and regeneration.Mesenchymal stem/stromal cells (MSCs) have emerged as promising candidates for periodontal regeneration, offering potential solutions to the limitations of traditional guided tissue regeneration (GTR) techniques. While GTR has shown effectiveness in reducing pocket depth and improving attachment gain, its narrow surgical indications and complications pose challenges. MSCs, with their capacity for self-renewal, multipotency, immunomodulation, and tissue regeneration, are considered valuable for regenerative medicine. MSCs can be derived from various sources, including non-odontogenic tissues like bone marrow, adipose tissue, and umbilical cord, as well as odontogenic tissues such as dental pulp, periodontal ligament, and apical papilla. Additionally, MSCs can be generated from induced pluripotent stem cells (iPSCs), which offer the advantage of unlimited expansion and reduced heterogeneity. However, iPSC-derived MSCs (iMSCs) require careful differentiation to avoid tumorigenic risks. MSCs are typically transplanted using scaffolds or scaffold-free methods, with biocompatible materials like collagen, chitosan, and bioceramics being commonly used. Scaffold-free techniques, such as cell sheet technology and clumps of MSCs/ECM complexes (C-MSCs), have shown promise in promoting periodontal tissue regeneration. 3D printing technologies are also being explored to create customized scaffolds for complex periodontal defects. Despite these advancements, challenges remain, including the need for standardized protocols, long-term storage of MSCs, and ensuring consistent therapeutic efficacy. MSCs also face immunological challenges, with allogeneic MSCs potentially triggering immune responses. However, iMSCs may offer improved immune compatibility. While preclinical studies demonstrate the potential of MSCs in periodontal regeneration, clinical trials are limited, and the long-term safety and effectiveness of MSC-based therapies remain to be fully established. Further research is needed to optimize MSC isolation, differentiation, and delivery methods, as well as to address the heterogeneity of MSC populations and their immune interactions. The future of periodontal regeneration may rely on a combination of MSC-based therapies, advanced scaffolding, and 3D printing technologies to achieve successful tissue repair and regeneration.