Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analysed for their effectiveness in virtual screening against four different targets: angiotensin-converting enzyme (ACE), cyclooxygenase 2 (COX-2), thrombin and human immunodeficiency virus 1 (HIV-1) protease. The relative performance of the tools was compared by examining their ability to recognise known active compounds from a set of actives and nonactives. Furthermore, we investigated whether the application of different virtual-screening methods in parallel provides complementary or redundant hit lists. Docking was performed with GOLD, Glide, FlexX and Surflex. The obtained docking poses were rescored by using nine different scoring functions in addition to the scoring functions implemented as objective functions in the docking algorithms. Ligand-based virtual screening was done with ROCS (3D-similarity searching), Feature Trees and Scitegic Functional Fingerprints (2D-similarity searching). The results show that structure- and ligand-based virtual-screening methods provide comparable enrichments in detecting active compounds. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary. These results suggest that a parallel application of different structure- and ligand-based virtual-screening methods increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign.