One of the most common and most difficult cases in dental clinical practice is the mandibular mesial tilted second molar. The treatment of changed environment caused of the tilted molar syndrome requires interdisciplinary dentofacial therapy. This literature review discusses the contents including the etiologies and signs of the tilted molar syndrome, periodontal tissues changed after molar uprighting, loading stress modification on periodontal structure after the replacement of prosthesis, the application of orthodontic and surgical approaches, and provide the clinical dentists with a comprehensive therapy concept for the tilted molar syndrome.