The systematic alteration of protein structure has now become possible with genetic engineering. Recent developments in techniques for the chemical synthesis of DNA fragments and in recombinant DNA technology have enabled the facile modification of proteins by highly specific mutagenesis of their genes. Enzymes with novel properties may be produced in large quantities from the mutant genes. Kinetic analysis of the mutant enzymes can be combined with high-resolution structural data from protein X-ray crystallography to provide direct measurements on the relationships between structure and function. In particular, the strength and nature of enzyme-substrate interactions and their roles in catalysis and specificity may be studied. The tyrosyl-tRNA synthetase from Bacillus stearothermophilus is being systematically analysed by site-directed mutagenesis. A fine-structure analysis is revealing the subtle roles of hydrogen bonding in catalysis and specificity. Modification of the residues that hydrogen-bond with ATP and tyrosine shows how the energetics must be analysed in terms of an exchange reaction with solvent water. Based on this idea, and structural data, an enzyme of vastly improved enzyme-substrate affinity has been engineered. There thus appear to be real prospects of engineering proteins of new specificities, activities and structural properties. Direct information is also being gathered on the nature of enzyme catalysis. For example, the catalysis of formation of Tyr-AMP from Tyr and ATP does not appear to use the classical mechanisms of acid-base or covalent catalysis. Instead, there just appears to be a binding site that stabilizes the high-energy pentacoordinate intermediate in the reaction.