Shape-based molecular similarity approaches have been established as important and popular virtual screening techniques. Recent applications have shown successful screening campaigns using different parameters and query selection. It is common sense that pure volume overlap scoring (or "shape-based screening") under-represents chemical or pharmacophoric information of a molecule. Using the "Directory of Useful Decoys" (DUD) as a benchmark set, we systematically evaluate how (i) the choice of query conformations, (ii) the selection of the active compound to be used as a query structure, and (iii) the inclusion of chemical information (i.e., the pharmacophoric properties of the query molecule) affect screening performance. Varying these parameters bears remarkable potential for improvements and delivers the best screening performance reported using these tools so far. From these insights, guidelines on how to reach optimum performance during virtual screening are developed.