Fold assignments for newly sequenced genomes belong to the most important and interesting applications of the booming field of protein structure prediction. We present a brief survey and a discussion of such assignments completed to date, using as an example several fold assignment projects for proteins from the Escherichia coli genome. This review focuses on steps that are necessary to go beyond the simple assignment projects and into the development of tools extending our understanding of functions of proteins in newly sequenced genomes. This paper also discusses several problems seldom addressed in the literature, such as the problem of domain prediction and complementary predictions (e.g., transmembrane regions and flexible regions) and cross-correlation of predictions from different servers. The influence of sequence and structure database growth on prediction success is also addressed. Finally, we discuss the perspectives of the field in the context of massive sequence and structure determination projects, as well as the development of novel prediction methods.