The large number of small organic compounds now available for drug-lead screening has led to numerous methods for classifying molecular similarity and diversity, the aim being to restore a balance between the quantity and drug-like quality of compounds in small-molecule libraries. Whereas structural and physicochemical attributes continue to be emphasized in compound selection for drug-lead screening, chemoproteomics--the use of biological information to guide chemistry--offers a highly efficient alternative to small-molecule characterization that can accelerate drug discovery in the post-genomic era.