Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase-2 (COX-2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource-intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data. The inclusion of full receptor and ligand flexibility into the molecular modeling of carborane-containing drug molecules may yield more definitive results, but is currently hindered by the lack of appropriate carborane force field parameters.