Metals are employed by all types of organisms to perform a remarkable array of functions that are critical for life. The concentrations of many are highly regulated through homeostatic mechanisms and pathways in which organisms selectively and correctly metallate metalloproteins. Along these pathways, metal‐mediated protein–protein interactions (i.e., those only occurring in the presence of the metal ion and through a direct interaction with it) contribute to select the correct route for metal transfer to the correct final destination; the metal is necessary for the interaction between the donor and the acceptor. The energetic contribution leading to the formation of detectable amounts of complex in the presence of the metal results from the involvement of amino acid ligands from both protein partners in the coordination sphere of the metal ion. In the case of Cu