Two orders of magnitude more protein sequences can be modeled by comparative modeling than have been determined by X-ray crystallography and NMR spectroscopy. Investigators have nevertheless been cautious about using comparative models for ligand discovery because of concerns about model errors. We suggest how to exploit comparative models for molecular screens, based on docking against a wide range of crystallographic structures and comparative models with known ligands. To account for the variation in the ligand-binding pocket as it binds different ligands, we calculate "consensus" enrichment by ranking each library compound by its best docking score against all available comparative models and/or modeling templates. For the majority of the targets, the consensus enrichment for multiple models was better than or comparable to that of the holo and apo X-ray structures. Even for single models, the models are significantly more enriching than the template structure if the template is paralogous and shares more than 25% sequence identity with the target.