Pb 2+ is known to displace physiologically-relevant metal ions in proteins. To investigate potential relationships between Pb 2+ /protein complexes and toxicity, data from the protein data bank were analyzed to compare structural properties of Pb 2+ - and Ca 2+ -binding sites. Results of this analysis reveal that the majority of Pb 2+ sites (77.1%) involve 2–5 binding ligands, compared with 6±2 for non-EF-Hand and 7±1 for EF-Hand Ca 2+ -binding sites. The mean net negative charge by site (1.7) fell between values noted for non-EF-Hand (1±1) and EF-Hand (3±1). Oxygen is the dominant ligand for both Pb 2+ and Ca 2+ , but Pb 2+ binds predominantly with sidechain Glu (38.4%), which is less prevalent in both non-EF-Hand (10.4%) and EF-Hand (26.6%) Ca 2+ -binding sites. A comparison of binding geometries where Pb 2+ has replaced Ca 2+ in calmodulin (CaM) and Zn 2+ in 5-aminolaevulinic acid dehydratase (ALAD) revealed protein structural changes that appear to be unrelated to ionic displacement. Structural changes observed with CaM may be related to opportunistic binding of Pb 2+ in regions of high electrostatic charge, whereas ALAD may bind multiple Pb 2+ ions in the active site. These results suggest that Pb 2+ adapts to structurally-diverse binding geometries and that opportunistic binding may play an active role in molecular metal toxicity.