The ability to predict the rate of permeation of new compounds across biological membranes is of high importance for their success as drugs, as it determines their efficacy, pharmacokinetics, and safety profile. In vitro permeability assays using Caco-2 monolayers are commonly employed to assess permeability across the intestinal epithelium, with an extensive number of apparent permeability coefficient () values available in the literature and a significant fraction collected in databases. The compilation of these values for large datasets allows for the application of artificial intelligence tools for establishing quantitative structure-permeability relationships (QSPRs) to predict the permeability of new compounds from their structural properties. One of the main challenges that hinders the development of accurate predictions is the existence of multiple values for the same compound, mostly caused by differences in the experimental protocols employed. This review addresses the magnitude of the variability within and between laboratories to interpret its impact on QSPR modelling, systematically and quantitatively assessing the most common sources of variability. This review emphasizes the importance of compiling consistent data and suggests strategies that may be used to obtain such data, contributing to the establishment of robust QSPRs with enhanced predictive power.