Metal-mediated base pairs are transition metal complexes formed from complementary nucleosides within nucleic acid double helices. Instead of relying on hydrogen bonds, they are stabilized by coordinative bonds. The nucleosides acting as ligands do not necessarily have to be artificial. In fact, several examples are known of naturally occurring nucleobases (e.g., thymine, cytosine) capable of forming stable metal-mediated base pairs that are highly selective towards certain metal ions. This chapter provides a comprehensive overview of metal-mediated base pairs formed from natural nucleosides or from closely related artificial nucleosides that are pyrimidine or purine derivatives. It addresses the different strategies that lead to the development of these base pairs. The article focuses on structural models for metal-mediated base pairs, their experimental characterization within a nucleic acid, and on their possible applications.