DNA shuffling is a powerful tool for protein engineering that allows the recombination of genes in vitro to generate libraries of hybrid proteins to screen for desired properties. However, the technique is limited by the requirement for high sequence homology between the parent genes. In this issue, Ostermeier et al. describe a method for generating hybrid proteins using more distantly related genes that may allow protein engineers to create a more diverse set of hybrid enzymes (see p. 1205 and Research News p.1159).