Periodontitis is a chronic infectious oral disease with a high prevalence rate in the world, and is a major cause of tooth loss. Nowadays, people have realized that the local microenvironment that includes proteins, cytokines, and extracellular matrix has a key influence on the functions of host immune cells and periodontal ligament (PDL) stem cells during a chronic infectious disease such as periodontitis. The above pathological process of periodontitis will lead to a defect of periodontal tissues. Through the application of biomaterials, biological agents, and stem cell therapy, guided tissue regeneration (GTR) makes it possible to reconstruct healthy PDL tissue after local inflammation control. To date, substantial advances have been made in periodontal GTR. However, the process of periodontal remodeling experiences complex microenvironment changes, and currently periodontium regeneration still remains to be a challenging feat. In this review, we summarized the main challenges in each stage of periodontal regeneration, and try to put forward appropriate biomaterial treatment mechanisms or potential tissue engineering strategies that provide a theoretical basis for periodontal tissue engineering regeneration research.