Interactions among the residues in the serine protease Asp-His-Ser catalytic triad, in the special environment of the enzyme-substrate complex, activate the nucleophilic potential of the seryl O gamma. In the subtilisin and trypsin families, the composition and arrangement of the catalytic triad do not vary significantly. However, the mechanisms of action of many other hydrolytic enzymes, which target a wide range of substrates, involve nucleophilic attack by a serine (or threonine) residue. Review of these enzymes shows that the acid-base-ser/thr pattern of catalytic residues is generally conserved, although the individual acids and bases can vary. The variations in sequence and organization illustrate the adaptability shown by proteins in generating catalytic stereochemistry on different main-chain frameworks.