Bifunctional reagents may be used to cross-link proteins (see Fig. 22.1). They may be homo-bifunctional (two identical reactive groups) or hetero-bifunctional, for example with a thiol- (maleimides) and an amino-specific end (NHS-ester). Intra-molecular cross-links are favoured over inter-molecular ones by low protein concentration, a high net charge of the protein (electrostatic repulsion) and by a high protein-to-reagent ratio. Since the cross-linking of monomers and oligomers follow a different time course the oligomeric state of proteins can be investigated by cross-linking. However, analytical ultracentrifugation and laser light scattering offer much higher precision.