Objective o explore the effect and mechanisms of transmembrane 4 super family (TM4SF) in digestive system cancer. Methods Articles were reviewed to discuss the biological characteristics of TM4SF in digestive system cancer. Results TM4SF played an important role in migration and invasion of digestive system cancer, including pancreatic cancer, gastric cancer, colorectal cancer, hepatic cancer, esophageal cancer, and so on. TM4SF modulated the cell biological activities by microdomains which were fixed on cell membrane, such as adhesion, migration, invasion, and proliferation. Conclusion TM4SF may be used to predict the metastasis and prognosis of digestive system cancer and may be the targets of therapy of it in the future.