The base moieties of nucleic acids react with a wide range of transition metal ions through formation of either coordinate or organometallic bonds. In many cases, the reactions are sufficiently selective toward a given nucleobase to serve as a basis for elucidation of sequence information. Two fundamentally different approaches can be envisaged. Firstly, a metallated nucleobase can engage in metal-mediated base pairing with a natural nucleobase of the opposite strand and this interaction can be quite distinct from canonical Watson–Crick base pairing in terms of both affinity and selectivity. Secondly, a heavy metal ion can act as a contrast-enhancing label, altering the physicochemical properties of a nucleobase to make it detectable against a background of unmodified nucleobases. The first approach has found use in oligonucleotide hybridization probes for the detection of single-nucleotide polymorphisms (SNPs) and the second one in electron microscopy or nanopore sequencing. The potential of metals in genotyping has been studied for more than half a century but never very intensively. This chapter attempts to bring together the scattered reports in this field and to identify the most promising achievements as well as challenges that need to be met.