Structural genomics projects aim to provide an experimental structure or a good model for every protein in all completed genomes. Most of the experimental work for these projects will be directed toward proteins whose fold cannot be readily recognized by simple sequence comparison with proteins of known structure. Based on the history of proteins classified in the SCOP structure database, we expect that only about a quarter of the early structural genomics targets will have a new fold. Among the remaining ones, about half are likely to be evolutionarily related to proteins of known structure, even though the homology could not be readily detected by sequence analysis.