Virtual screening technology permits rapid sieving through large screening compound collections and virtual compound libraries. It fuels hit identification projects by providing isofunctional bioactive compounds that are structurally unrelated to the original query. Such valuable starting points for lead discovery can be obtained by pharmacophore-based similarity searching, which has emerged as a preferred concept for retrieving novel bioactive chemotypes with minimal experimental effort. This review highlights ‘fuzzy’ pharmacophore concepts and applications in hit finding and molecular de novo design.