+9131The study of diverse biological phenomena by chemical cross-linking tech nology has greatly intensified during the past 5 years. A number of excel lent, timely, and chemically oriented reviews of the cross-linking literature have appeared (4, 68, 87). Therefore, we have attempted to present a critical evaluation of the principles and strategies that govern the applica tion of cross-linking technology to the solutions of biological problems.The use of chemical cross-linking reagents as molecular rulers in the determination of quaternary structure in oligomeric protein complexes in solution and in membranes has enjoyed wide application. Another as pect of cross-linking technology is the exploitation of heterobifunctional reagents to identify ligand-binding components in complex biological sys tems. It is often difficult to determine how proteins function in multicompo nent, complex systems. The classical biochemical approach of isolation and characterization of protein components does not always reveal tran sient interactions or migratory behavior of proteins, which occur in the natural environment of the cell. The covalent linkage of a ligand to a specifi c protein provides a strategy fo r visualizing this behavior. PHOTO REACTIVE CROSS-LINKING REAGENTSArylazide reagents that can be employed fo r photochemical attachment of ligands to recognition sites on macromolecules are described in Table