Multiple screening techniques have been developed to gain simplicity and rapidness in prediction of human intestinal permeability. The most extensively used method for years has been the Caco-2 cell monolayers. Are the less time- and resource-consuming artificial membranes and computational-based predictions on their way to replace the Caco-2 cells? The importance of mechanistic approaches and correct interpretation of the data using the techniques available is compared and discussed in this article.: