Electronic structures of Zn2+ and Cd2+ thiolate clusters found in metallothioneins (MT) have been obtained using density functional theory. We have found that the inherent asymmetry of cluster architectures gives rise to seven distinct metal sites. Whereas the non-strained bond lengths of such tetrathiolate complexes are found to be 2.60 Å and 2.39 Å for Cd–S and Zn–S, in the MT clusters four characteristic terminal and bridging bonds are observed with average lengths 2.55 Å (Cd–St); 2.35 Å (Zn–St); 2.62 Å (Cd–Sb); and 2.42 Å (Zn–Sb). For each stoichiometry of Zn2+ and Cd2+, all possible isomers have been characterized and ranked according to relative free energy and metal ion selectivity. The most stable distribution at low Cd2+ concentration is computed to be Zn4 + CdZn2, whereas at 2 : 1 Cd2+ : Zn2+ concentration, only heteroclusters are thermodynamically stable, explaining experimental data. The presence of two different clusters in MTs must and can be rationalized already in their intrinsic differences. The results indicate that the asymmetry allows for Zn2+ transfer to various molecular targets having different thresholds for Zn2+ binding, while maintaining detoxification sites.