Site-directed mutagenesis of amino acids in the active site of an enzyme can yield mutant proteins with dramatically altered substrate specificity. In the past year, several enzymes have been successfully engineered with desired changes in specificity. Although most of these designs have been made on the basis of homology to closely related enzymes with different specificities, preliminary work suggests that the computer-based design of altered enzymes may soon be feasible. The development of generalized genetic selections for mutant proteins with changed binding specificity may avoid the problem of rational design and permit the rapid synthesis of enzymes with novel substrate-binding properties.