Since the introduction of fine needle aspiration biopsy (FNAB) in the 1970's, a preoperative diagnostic technique for thyroid follicular carcinoma has long been awaited. Many markers that distinguish follicular carcinomas from adenomas have been reported; however, most of them have not been confirmed to be beneficial for clinical use. Trefoil factor 3 (TFF3) is a relatively new family of peptides that bears the three-loop trefoil domain. Several groups have reported that the suppression of TFF3 mRNA expression is related to malignant characteristics of thyroid follicular cell-derived tumors and the expression level of TFF3 mRNA is the most promising indicator for diagnosing follicular carcinoma. Development of TFF3-based diagnostic methods is now ongoing and it may not be long before thyroid follicular carcinoma can be diagnosed preoperatively using an aspirated sample from the tumor.