Food and medicinal substances(FAMS) with both edible and medicinal uses have a long history in China, being an important part of China's excellent traditional culture and traditional Chinese medicine(TCM). The legal management of FAMS is in the form of catalogue, which has a history of nearly 40 years. More than 100 substances have been included in the China's FAMS catalogue. According to the Regulation of Food and Medicinal Substances Catalogue, safety assessment is a basis for substances to be included in the catalogue. The safety assessment of FAMS should follow the principles and requirements of food safety risk assessment. However, FAMS is a complex mixture, and the nature and data adequacy of the assessed substance should be comprehensively considered. Different eva-luation models and methods should be selected according to the principle of case analysis. With the development of next-generation technologies such as big data, artificial intelligence, high-throughput and high-content in vitro testing, and computational toxicology and the trend of increasing edible substances with medicinal effects applying for the inclusion in the China's FAMS catalogue, the methods of risk assessment are applied in the management of FAMS, novel food products, and local characteristic food products, playing a scientific role. This paper systematically reviews the methods, challenges, and prospects of safety assessment of FAMS.