Abstract: Foam fractionation has great potential in reducing the costs of protein separation due to its advantages of high efficiency at low concentrations, low costs and free pollution. However, protein denaturation induced by the gas-liquid interface can significantly reduce the separation performance of proteins, which severely limits the industrial applications of foam fractionation in protein separation. To solve this problem, based on the listed common phenomena of protein denaturation in foam fractionation, the recent researches on the denaturation mechanisms were firstly described at molecular and foam levels. In the meanwhile, the methods for molecular-level studies on protein denaturation in foam fractionation were summarized, analyzed and compared. Subsequently, the methods for preventing the protein denaturation were divided into two types:inhibition before separation and renaturation after separation. Based on their recent studies, the two types of methods were analyzed and compared, and the latter was suggested to be more effective. Finally, molecular-level studies of foam fractionation of proteins were considered to be of serious lack and resolving contradictions between denaturation induced by the gas-liquid interface and interfacial adsorption of proteins was regarded as the key to improving their foam fractionation performances. Accordingly, possible future directions of research were suggested.