Smectites, members of the 2:1 layer silicate family, share the common feature that two tetrahedral sheets sandwich a sheet of octahedrally coordinated metal ion. The diversity of the members of the 2:1 layer silicates occurs because of their capacity for isomorphous substitution of various cations in the octahedral or tetrahedral sheets. Substitution of a divalent metal ion (such as Mg2+) for the trivalent Al3+ or a trivalent metal ion (such as Al3+) for the tetravalent silicon results in a net negative charge, which then undergoes interaction with positive ions (the exchangeable cations) to form an interlayer hydrated phase. Local density functional (LDF) calculations were employed to model isomorphous substitution of Al3+ by Na+, K+, Mg2+, Fe2+, and Fe3+ in the octahedral layer of a dioctahedral smectite clay such as montmorillonite. The energies of the isomorphous substitution were then compared with the experimental observation. The ordering for successful substitution is Al3+ > Fe3+ > Mg2+ > Fe2+ > Na+ < K+. This ordering is consistent with experimental observation. The vibrational frequencies for the isomorphous substituted systems were calculated by LDF calculation and were compared with the experimental IR results. The results match very well with experiment. This understanding will help in successful prediction of the catalytic activity of smectite clays.