The intestine is a complex organ formed of different types of cell distributed in different layers of tissue. To minimize animal experiments, for decades, researchers have been trying to develop in vitro/ex vivo systems able to mimic the cellular diversity naturally found in the gut. Such models not only help our understanding of the gut physiology but also of intestinal toxicity. This review describes the different systems used to evaluate the effects of drugs/contaminants on intestinal functions and compares their advantages and limitations. The comparison showed that the organotypic model is the best available model to perform intestinal toxicity studies, including on human tissues.