Divalent manganese, magnesium, and zinc fill unique roles in biological systems, despite many apparently similar chemical properties. A comparison of the liganding properties of divalent manganese, magnesium, and zinc has been made on the basis of data on crystal structures (from the Cambridge Structural Database and the Protein Databank) and molecular orbital and density functional calculations. The distribution of coordination numbers for divalent manganese in crystal structure determinations, and the identities of ligands, have been determined from analyses of data derived from the structural databases. Enthalpy and free energy changes for processes such as loss of water or ionization of water from hydrated cations have been evaluated from computational studies. The energy penalty for changing the hexahydrate of divalent manganese to a pentahydrate with one water molecule in the second coordination shell is intermediate between the high value for magnesium and the low value for zinc. The preferred coordination number of divalent manganese is six, as it is for magnesium, while the preferred coordination is less definite for zinc and ranges from 4 to 6. Magnesium generally binds to oxygen ligands, and divalent manganese behaves similarly, although it is more receptive of nitrogen ligands, while zinc prefers nitrogen and sulfur, especially if the coordination number is low. The slightly lower discrimination between nitrogen and oxygen of divalent manganese, compared to magnesium, was apparent both in the energetics of competition of these cations for water and ammonia and from ligand binding profiles in the crystallographic databases.