It is generally admitted in drug research that the passage of molecules across cellular barriers increases with lipophilicity and that the most lipophilic compounds will have the highest intestinal absorption. Using two in vitro models of intestinal epithelium, we presently demonstrate that this concept is not always valid and that highly lipophilic compounds display a low transepithelial permeability. We used epithelial cell lines grown on permeable filters to measure in vitro the transepithelial permeability of various molecules. The octanol/buffer distribution coefficient of the drugs (Do/b) was taken as an index of lipophilicity. When log Do/b values were lower than 3.5, the transepithelial permeability coefficient increased with the lipophilicity. But for log Do/b values ranging from 3.5 to 5.2, the transepithelial permeability coefficient decreased with increasing lipophilicity. Identical results were observed with two differentiated intestinal epithelial cell lines (HT29-18-C1 and Caco-2) and in unstirred or agitated conditions. The results show that an octanol/buffer distribution coefficient value around 3000 corresponds to an optimal transepithelial passage of drugs and that too high a lipophilicity can result in low intestinal epithelial permeability and in low oral absorption.