A new hypothesis describing the role of the redox inactive Ca2+ ion in the expression of physiological oxidative damage is described. The hypothesis is based on the optimization of the chelation characteristics of iron complexes for pro-oxidant activity. In a previous investigation it was found that an excess of ligand kinetically hindered the Fenton reaction activity of the FeII/III EDTA complex (Bobier et al. 2003). EDTA, citrate, NTA, and glutamate were selected as models for the coordination sites likely encountered by mobile iron, i.e. proteins. The optimal [EDTA]:[FeIII] ratio for Fenton reaction activity as measured by electrocatalytic voltammetry in a solution was found to be 1:1. An excess of EDTA in the amount of 10:1 [ligand]: [metal] suppresses the Fenton reaction activity to nearly the control. It is expected that the physiological coordination characteristics of mobile Fe would have a very large excess of [ligand]:[metal] and thus not be optimized for the Fenton reaction. Introduction of Ca2+ in to a ratio of 10:10:1 [Ca2+]:[EDTA]:[FeIII] to the system reinvigorated the Fenton reaction activity to nearly the value of the optimal 1:1 [EDTA] :[FeIII] complex. The pH distribution diagrams of Ca2+ in the presence of EDTA and FeII/III indicate that Ca2+ has the ability to uptake excess EDTA without displacing either FeII of FeIII from their respective complexed forms. The similarity in the presence for hard ligand sites albeit with a lower binding constant for Ca2+ accounts for this action.