Small-molecule microarrays have been used to discover biologically active small molecules in collections of synthetic compounds. Here we utilize a versatile isocyanate chemistry to immobilize extracts from microorganisms in a microarray format. Specific bioactive small molecules are detected in crude extracts of Streptomyces hygroscopicus, and the amount of specific to nonspecific binding of a protein to an immobilized compound on a microarray can be estimated. These natural product-extract microarrays (NPEMs) provide new tools for characterizing the metabolic products of organisms and for discovering biologically active small molecules from nature.