The Caco-2 cell model has been widely used to assess the permeability of drug candidates. It has provided a high throughput in vitro platform, functionally resembling the enterocytes. Since the oral route is the most preferred for drug administration, the Caco-2 cell model acts as a very important tool to elucidate the oral “druggability” of a molecule by providing a fairly reliable estimate of its permeability through the intestinal membrane. Despite its shortcomings (the lack of a mucus layer, long cultivation period, inter-lab variability, and differences in expression of enzymes, transporters, and tight junction complexes) it remains heavily used due to its reliability, predictive performance, and wide acceptance. Various modifications have been made: co-culturing with other intestinal cells, applying biosimilar mucus, reducing culturing time, combining Caco-2 monolayer with the dissolution apparatus, enhancing protein expression, and redesigning the sampling apparatus. These modifications are intended to overcome some of the shortcomings of the Caco-2 model in order to make its use easier, quicker, economical, and more representative of the intestine. The aim of this review is to discuss such modifications to enhance this model’s utility, predictive performance, and reproducibility.