In classic work, Kuntz et al. (Proc. Nat. Acad. Sci. USA 1999, 96, 9997-10002) introduced the concept of ligand efficiency. Though that study focused primarily on drug-like molecules, it also showed that metal binding led to the greatest ligand efficiencies. Here, the physical limits of binding are examined across the wide variety of small molecules in the Binding MOAD database. The complexes with the greatest ligand efficiencies share the trait of being small, charged ligands bound in highly charged, well buried binding sites. The limit of ligand efficiency is -1.75 kcal/mol·atom for the protein-ligand complexes within Binding MOAD, and 95% of the set have efficiencies below a "soft limit" of -0.83 kcal/mol·atom. On the basis of buried molecular surface area, the hard limit of ligand efficiency is -117 cal/mol·Å(2), which is in surprising agreement with the limit of macromolecule-protein binding. Close examination of the most efficient systems reveals their incredibly high efficiency is dictated by tight contacts between the charged groups of the ligand and the pocket. In fact, a misfit of 0.24 Å in the average contacts inherently decreases the maximum possible efficiency by at least 0.1 kcal/mol·atom.