Abstract: Trefoil factor (TFF) family is a group of peptides with one or several trefoil factor domains in their structure, which are highly conserved in evolution, and are characterized by heat and enzymatic digestion resistance. The mammalian TFFs have three members（TFF1-3）, and the gastrointestinal tract and the airway system are major organs of their expression and secretion. At certain physiological conditions, with a tissue-specific distribution，TFF plays an important role in mucosal protection and wound healing. But in the malignant tissues, TFF is widely expressed，correlated strongly with the genesis, metastasis and invasion of tumor cells. These phenomena indicated that TFF may be a possible common mediator of oncogenic responses to different stimuli. The biological functions of TFF involve complex regulatory processes. Single chain TFF may activate cell membrane receptors and induce specific signaling transduction. On the other hand, TFF can form a complex with other proteins to exert its biological effects. In clinical medicine, TFF is primarily applied as drugs in the mucosal protection, in the prevention and the treatment of mucosal damage-related diseases and as pathological biomarkers of tumors. At present the first hand actions and the molecular mechanisms related to TFFs are still the major challenges in TFF research. Furthermore, the discovery of the naturally occurring complex of TFF and crystallins is highly valuable to the understanding of the biological functions and action mechanisms of TFF.