The physicochemical basis for epitaxial stabilization of coincident molecular overlayers is illustrated by comparison of optimum overlayer-substrate configurations calculated with potential energy (PE) methods and a simple geometric lattice misfit modeling algorithm (EpiCalc) that neglects molecular orientations and intermolecular potentials. Using â-bis(ethylenedithio)tetrathiafulvalene triiodide (â-ET2I3), perylenetetracarboxylic diimide (PTCDI), and perylenetetracarboxylic dianhydride (PTCDA) overlayers on a graphite substrate as examples, both methods predict identical optimum azimuthal overlayer orientations for each overlayer that also agree with experimental observations. PE calculations for three hypothetical PTCDA overlayers, with identical lattice parameters but different molecular orientations, predict coincidence at the same azimuthal orientation for all overlayers. Identical results are achieved for PE calculations performed with this lattice when it is occupied by naphthalenetetracarboxylic dianhydride (NTCDA) molecules or argon atoms. These results demonstrate that the epitaxial orientation of coincident overlayers is governed more by geometric lattice matching than specific molecule-substrate interactions and that unambiguous determination of the optimum azimuthal orientation relies on establishing the phase relationship between several overlayer supercells and the substrate. In the case of PE methods, calculations with large overlayer sizes are computationally prohibitive and the energy differences between alternative orientations typically are smaller than the confidence limits of the method. In contrast, the calculation time required by EpiCalc is independent of overlayer size, providing a significant advantage over PE methods with respect to computational speed while enabling unambiguous assignment of the optimum coincident configuration. The reliability of EpiCalc in predicting observed epitaxial overlayer orientations indicates that geometric lattice misfit modeling can be used to screen efficiently for the most favorable epitaxial configuration (overlayer lattice parameters and azimuthal angle), which can then be used in subsequent PE calculations that allow for other degrees of freedom such as molecular orientation.