The interactions of two diphosphonic acid based surfactants, namely alkylimino-bis-methylene-diphosphonic acid (IMPA-8) and 1-hydroxy-alkylidene-1,1-diphosphonic acid (Flotol-8), with three calcium minerals, fluorite, calcite, and fluorapatite, were quanitfied on the basis of molecular modeling computations. Both force field (UFF) and semiempirical quantum mechanical (MNDO) methods were employed for this purpose. The results of theoretical calculations in terms of the prediction of the order of response of these three minerals to flotation with diphosphonic acid reagents were found to match remarkably well with the experimental microflotation test results. The utility and power of this approach in the design/screening of surfactant molecules for flotation separation are demonstrated, and its tremendous implications for the industry are discussed.