Cross-linking and cross-bridging are highly versatile methods of creating composite protein structures with desired mechanical properties such as deformation endurance, elasticity, extensibility, and stability under intensive and repetitive sheering forces. Cross-linking and cross-bridging are distinguished by the bonds that hold the structural components together. Cross-linking implies a covalent association, whereas cross-bridging depends on biological recognition, in which hydrogen bonding, ionic, and hydrophobic interactions predominate. Cross-bridged structures are found in all living systems. Cytoskeletal interaction, cell invasion by pathogens, fertilization, and cellulosomal degradation of cellulose are all examples of biological processes in which cross-bridging proteins play a key role. This article will review the different types of biological cross-bridging proteins that are known and discuss their emerging nano- and biotechnological applications.