The health benefits of pomegranate consumption have been known since the antiquity. More recently, the biological activities of pomegranate, including its anti-bacterial, antioxidant, anti-inflammatory and anticarcinogenic properties, have raised great interests in the scientific community and they have been the subject of a large number of scientific studies. Several phenolic compounds are present in various parts of the fruit, of which ellagitannins, hydrolysable tannins considered responsible for most health benefits of pomegranate. Despite all these efforts, the actual effectors remain unidentified and the mechanisms of action only partially elucidated. This is probably due to the complex catabolic pathway of these molecules that takes place in the gastrointestinal tract, involving both microbial and cellular modifications before entering the bloodstream. The diversity of the intestinal microbiota in the human population leads to the production of different metabolites in individuals, contributing to the heterogeneity of the response to dietary pomegranate assumption. This complex situation determines the need for special attention in designing studies on the action of ellagitannins on both cell cultures and animal models.