Food-intestine interaction study has always been a hot topic in food science and nutrition due to diverse physiological functions of intestine. Compared to expensive animal models with limited screening capabilities, the simple, reliable and highly reproducible intestinal cell models are widely used in food-intestine interaction study. There are many functional cell models used to simulate the intestine in vitro, among which the Caco-2 cell model is one of the most widely used and classical models. Recently years, the differentiated Caco-2 cell model has been greatly developed due to the development of various technologies, which not only overcomes the limitations of the traditional model, but also further broadens its application. This review aims to overview the current applications of the differentiated Caco-2 cell model as a specialized model of intestinal cells in vitro, as well as new approaches solving the existing challenges of utilization, which can guide its future trends in interaction between food factors and the intestine. Key findings and conclusions: With high flexibility, high repeatability and low cost, the differentiated Caco-2 cell model has been applied to a variety of intestinal studies including intestinal absorption, intestinal transport, intestinal metabolism, intestinal barrier, intestinal immunity and intestinal adhesion. Furthermore, future study should break limitations of traditional models with the help of automation, biochemistry, molecular biology and cells co-culture, so as to make it more closer to the internal environment without sacrificing its simplicity and reliability, and more suitable for cost-effective large-scale analysis of food-intestine interaction. •Caco-2 monolayer express some structural and functional characteristics of intestine.•Caco-2 cell models applied to nutrition absorption, transport and metabolism in gut.•Effects of food factors on intestinal functions were study using Caco-2 cell models.•Molecular biology and automation are future trends to optimize Caco-2 cell models.