This Perspective outlines the coordinating properties of lead(II), to some extent in comparison with related metal ions like Ca²⁺, Zn²⁺ or Cd²⁺. It is worth noting that the affinity of Pb²⁺ towards phosphate residues corresponds to that of Cu²⁺. Furthermore, the binding tendency of Pb²⁺ towards thiophosphate groups as present in methyl thiophosphate (MeOPS²⁻) or uridine 5′-O-thiomonophosphate (UMPS²⁻) is compared with that of the parent ligands, that is, methyl phosphate (CH₃OPO₃²⁻) and uridine 5′-monophosphate (UMP²⁻). The replacement of an O by a S atom makes the monoprotonated thiophosphate group considerably more acidic [compared to ROP(O)₂⁻(OH)], but at the same time its affinity for Pb²⁺ increases tremendously: more than 99% of Pb²⁺ is S-bound. This is very different if the coordinating properties of uridylyl-(5′→3′)-[5′]-uridylate (pUpU³⁻) and P-thiouridylyl-(5′→3′)-[5′]-uridylate (pUp_(S)U³⁻) are compared. The phosphate-coordinated Pb²⁺ forms a 10-membered chelate with one of the two terminal O atoms of the phosphodiester linkage, which reaches a formation degree of about 90% in Pb(pUpU)⁻. However, in Pb(pUp_(S)U)⁻ the formation degree of the chelate is reduced to about half in accordance with the fact that now only one terminal O atom is available in the thiophosphate diester bridge, that is, Pb²⁺ coordinates to this O showing no affinity for S in ROP(O)(S)⁻OR′. These observations are ascribed to the properties of the Pb²⁺ lone pair, which shapes the Pb²⁺ coordination sphere; its role is discussed further in this Perspective and a caveat is made regarding Pb²⁺ binding to a thiophosphate diester linkage.