The concept of maintaining spatial congruence between substrate binding site and regions of greatest enantiodifferentiation to ensure efficient chiral recognition in host-guest chemistry is described in this paper. Regions of maximum chiral recognition were located by determining Boltzmann weighted intermolecular energies of chiral probe molecules placed at well-defined grid points around a molecule and then evaluating the magnitude of (dis)similarity of interaction at each grid point. Sites having little or no energy differences between enantiomeric probes are nondiscriminatory while those of greatest energy difference correspond to regions of maximum chiral discrimination. Seven analyte molecules containing a diverse set of organic functional groups were evaluated when binding to permethylated beta-cyclodextrin, a popular chiral stationary phase used in chromatography. The preferred binding site for host-guest association is the interior of the cyclodextrin, and the region of maximum discrimination is found to coincide with this location for all analytes studied. Forcing the guests to bind to the exterior of the macrocycle by blocking the interior of the cyclodextrin is predicted to reduce or eliminate resolution. A literature report confirming this prediction is cited.