Threshold of toxicological concern (TTC) is a scientific and practical method for the food safety risk assessment of chemicals, and also an useful tool for the identification and screening of chemicals with risk assessment priority. However, there were still controversial opinions concerning the application of this method, which was established to provide risk characterization on the bases of chemical structures whereas in the lack of conventional toxicological data. Here, we reviewed the principles, critical factors, and recent progress in the application of TTC method, to explore and summarize the critical aspects that need particular considerations in the risk assessment of chemicals.