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 +‐trafficking pathways, copper‐mediated protein–protein interactions have been conserved throughout evolution and can be exploited for a variety of cellular functions – from copper incorporation into cellular organelle or copper enzymes, to metal detoxification and regulatory roles in protein trafficking. NMR turns out to be the preferential tool to characterize these kinds of metal‐mediated interactions, in such a way as to be able to elucidate the aforementioned functional processes at the molecular level. The aim of this chapter is to present and discuss metal‐mediated interactions, to address an NMR‐based strategy for the structural determination of such complexes (which are at equilibrium with the free proteins with which they rapidly interconvert), and to provide troubleshooting. These aspects are illustrated with a recent example from our own research in studying copper‐mediated protein–protein complexes.