Protein design has become a powerful approach for understanding the relationship between amino acid sequence and 3-dimensional structure. In the past 5 years, there have been many breakthroughs in the development of computational methods that allow the selection of novel sequences given the structure of a protein backbone. Successful design of protein scaffolds has now paved the way for new endeavors to design function. The. ability to design sequences compatible with a fold may also be useful in structural and functional genomics by expanding the range of proteins used for fold recognition and for the identification of functionally important domains from multiple sequence alignments.