Heterobi- and multimetallic complexes providing close proximity between several metal centers serve as active species in artificial and enzymatic catalysis, and in model systems, showing unique modes of metal-metal cooperative bond activation. Through the rational design of well-defined, unsymmetrical ligand scaffolds, we create a convenient approach to support the assembly of heterometallic species in a well-defined and site-specific manner, preventing them from scrambling and dissociation. In this perspective, we will outline general strategies for the design of unsymmetrical ligands to support heterobi- and multimetallic complexes that show reactivity in various types of heterometallic cooperative bond activation. Unsymmetrical ligand scaffolds bridging two or more different metals in a site-selective manner offer a convenient approach to utilize metal-metal cooperation for bond activation.