Tryptophan synthase is a classic enzyme that channels a metabolic intermediate, indole. The crystal structure of the tryptophan synthase α₂β₂ complex from Salmonella typhimurium revealed for the first time the architecture of a multienzyme complex and the presence of an intramolecular tunnel. This remarkable hydrophobic tunnel provides a likely passageway for indole from the active site of the α subunit, where it is produced, to the active site of the β subunit, where it reacts with L‐serine to form L‐tryptophan in a pyridoxal phosphate‐dependent reaction. Rapid kinetic studies of the wild type enzyme and of channel‐impaired mutant enzymes provide strong evidence for the proposed channeling mechanism. Structures of a series of enzyme‐substrate intermediates at the α and β active sites are elucidating enzyme mechanisms and dynamics. These structural results are providing a fascinating picture of loops opening and closing, of domain movements, and of conformational changes in the indole tunnel. Solution studies provide further evidence for ligand‐induced conformational changes that send signals between the α and β subunits. The combined results show that the switching of the enzyme between open and closed conformations couples the catalytic reactions at the α and β active sites and prevents the escape of indole. © 2001 John Wiley & Sons, Inc. and The Japan Chemical Journal Forum Chem Rec 1:140–151, 2001*