Objectives Mesenchymal stem cells (MSCs) are characterized by the potential to differentiate into multiple cell lineages, high proliferation rates, and self-renewal capacity, in addition to the ability to maintain their undifferentiated state. The criteria used for the identification of MSCs include the positive expression of specific surface antigens, such as CD73, CD90, CD105, CD44, CD146, STRO-1, CD166, NANOG, and OCT4. The aim of this review was to explore the literature on markers able to identify MSCs and the presence of these cells in the healthy periodontal ligament and chronic periapical lesions (CPLs), highlighting their role in regenerative medicine and implications in the evolution of these lesions. Study Design Narrative literature review searching the PubMed and Medline databases was done. Articles published in English between 1974 and 2020 were retrieved. Results The included studies confirmed the presence of MSCs in the healthy periodontal ligament and in CPLs. Several surface markers are used for the characterization of these cells, which, although not specific, are effective in cell recognition. Conclusions MSCs participate in tissue repair, exerting anti-inflammatory, immunosuppressive, and proangiogenic effects, and are therefore involved in the progression and attenuation of CPLs or in the persistence of these lesions. Mesenchymal stem cells (MSCs) are characterized by the potential to differentiate into multiple cell lineages, high proliferation rates, and self-renewal capacity, in addition to the ability to maintain their undifferentiated state. The criteria used for the identification of MSCs include the positive expression of specific surface antigens, such as CD73, CD90, CD105, CD44, CD146, STRO-1, CD166, NANOG, and OCT4. The aim of this review was to explore the literature on markers able to identify MSCs and the presence of these cells in the healthy periodontal ligament and chronic periapical lesions (CPLs), highlighting their role in regenerative medicine and implications in the evolution of these lesions. Narrative literature review searching the PubMed and Medline databases was done. Articles published in English between 1974 and 2020 were retrieved. The included studies confirmed the presence of MSCs in the healthy periodontal ligament and in CPLs. Several surface markers are used for the characterization of these cells, which, although not specific, are effective in cell recognition. MSCs participate in tissue repair, exerting anti-inflammatory, immunosuppressive, and proangiogenic effects, and are therefore involved in the progression and attenuation of CPLs or in the persistence of these lesions.