Correctly ranking protein ligand interactions with respect to,overall tree:. energy of binding is a grand challenge for virtual drug design. Here we compare the performance of various quantum chemical approaches for tackling this so-called "scoring" problem. Relying on systematically generated benchmark sets of ligand model complexes based on the PDBbind database, we show that the performance depends first of all on the general level of theory. Comparing classical molecular mechanics (MM), semiempirical quantum mechanical (SQM), and density functional theory (DFT) based methods we find that enhanced SQM approaches perform very similar to DFT methods and substantially different from MM potentials.