As a vitro absorption model, the Caco-2 cells originate from a human colon adenocarcinomas and can differentiate into a cell layer with enterocyte-like features. The Caco-2 cell model is popularly applied to explore drug transport mechanisms, to evaluate the permeability of drug and to predict the absorption of drugs or bioactive substances in the gut. However, there are limitations to the application of Caco-2 cell model due to lack of a mucus layer, the long culture period and the inability to accurately simulate the intestinal environment. The most frequent way to expand the Caco-2 cell model and address its limitations is by co-culturing it with other cells or substances. This article reviews the culture methods and applications of 3D and 2D co-culture cell models established around Caco-2 cells. It also concludes with a summary of model strengths and weaknesses.