Scope and Method of Study. The requirement of calcium in the sequence resulting in the release of histamine from mast cells has been long known. Magnesium is an unsuitable substitute. Few structural models are available from which to infer differences between calcium and magnesium in bonding interactions and geometries during their respective complexation with common allergens. To elucidate a role for calcium in the histamine release sequence, a series of complexes were synthesized of calcium and magnesium and appropriate low molecular weight compounds. The interaction of calcium with inhibitors and with histamine itself were examined. The possible role of zinc as a structural cofactor for calcium binding was tested. Eighteen crystalline materials were subjected to single crystal X-ray examination. From these results, possible modes of calcium involvement in the histamine release sequence may be derived. Findings and Conclusions. Eighteen new compounds were examined by single crystal X-ray diffraction. Calcium and magnesium bind directly to low molecular weight allergens, but the two cations exhibit marked differences in binding and geometry. Calcium is bound in clusters and linear polymeric arrays by bridging ligands. Calcium always includes water molecules in its binding sphere. Calcium binds to ligands maximizing use of ligation sites. The calcium bound ligand array presents a nonpolar face to the surrounding environment. Magnesium binds to six ligands, displaying little distortion from octahedral geometry, often exhibiting only second sphere interactions with allergens. Magnesium clusters exist in isolation without bridging or multidentate ligation. These differences must represent the underlying reasons for differentiation between calcium and magnesium in many biological processes. Calcium has been shown to complex with monovalent histamine molecules. Calcium binding to an inhibitor of histamine release has been shown to present a polar surface to the environment. Zinc does not co-crystallize with calcium in complexes to allergens. Structural knowledge of calcium and magnesium in low molecular weight allergen complexes has been increased. Speculation as to the types of roles calcium may play in the release of histamine has a broader basis.