In the pharmaceutical industry, determination of chemical stability of metal ion-drug which is indicative of physicochemical properties, is very important. The clinical use of experimental chelating agents requires extensive preclinical pharmacological and toxicological assessment in multiple animal models which all of those, increase cost. Consequently, theoretical calculations prior to the experimental studies, can be worthwhile and save time and cost. In recent years, computational chemistry is a very powerful tool to design and development of new chelating agents for removal of Fe3+ metal ion. The quantum mechanical (QM) methods include the calculation of the binding free energies of Fe3+chelating agent complexes in the solution, makes it possible to compare the affinity and selectivity of chelating agents against Fe3+. Among these methods, density functional (DFT) methods provide a highly accurate to study such systems. In this book, we discuss recent developments in the application of DFT methods for investigation of the interactions between Fe3+ and hydroxypyridinone derivatives as chelating agents for treatment of iron overload disease.