Enzymatic catalysis relies on the action of the amino acid side chains arrayed in the enzyme active sites. Usually, only two or three 'essential' residues are directly involved in the bond making and breaking steps leading to product formation. For the past 20 years, enzymologists have been addressing the role of such residues by changing them into chemically inert side chains. Removal of an 'essential' group often does not abolish activity, but can significantly alter the catalytic mechanism. Such results underscore the sophistication of enzyme catalysis and the functional plasticity of enzyme active sites.