Modeling of experimental X-ray diffraction (XRD) patterns represents the optimum approach to the structure determination of mixed-layer structures (MLSs) that are commonly found in natural clay-rich samples. This approach allows for a detailed structural characterization of both pure and mixed-layer clay phases and for a semi-quantitative phase analysis in complex mixtures. The two informations are essential to gain new insight into the actual nature of reactions taking place in geological environments. Significant new findings obtained at different scales (from that of the particle to that of the elementary layer) on the actual structure of MLSs by modeling XRD profiles are reported.