Virtual screening benchmarking studies were carried out on 11 targets to evaluate the performance of three commonly used approaches: 2D ligand similarity (Daylight, TOPOSIM), 3D ligand similarity (SQW, ROCS), and protein structure-based docking (FLOG, FRED, Glide). Active and decoy compound sets were assembled from both the MDDR and the Merck compound databases. Averaged over multiple targets, ligand-based methods outperformed docking algorithms. This was true for 3D ligand-based methods only when chemical typing was included. Using mean enrichment factor as a performance metric, Glide appears to be the best docking method among the three with FRED a close second. Results for all virtual screening methods are database dependent and can vary greatly for particular targets.