Although binding often comes with a local entropic cost, not all binding events have large overall entropic penalties. A significant contributor to counter the cost is surely the liberation of ordered water molecules in the unbound state; however, even after accounting for solvation changes, the contributions of protein conformational entropy can even favor binding . This finding raises the hypothesis that nature counters the entropic penalty incurred at the binding site by modulating entropy elsewhere in the protein. Substantial evidence suggests that proteins have evolved to redistribute entropy from the binding site upon ligand interaction. This phenomenon, which we term spatial entropic redistribution, involves countering local ordering, manifested as a loss of entropy at the binding site, with an increase in disorder at more distant sites, reducing the overall change in conformational entropy. Importantly, this is not a "zero sum" compensation, as in classic entropyenthalpy compensation , but rather spatial entropy redistribution is an important mechanism for reducing the impact of unfavorable local entropic changes and, therefore, improving the overall free energy of binding. While pre-paying entropic penalties result from ordering a specific binding site in the ground state, spatial entropic redistribution results from distal sites increasing entropy in response to a local reduction at the binding site. The change in entropy from distal sites can, therefore, partially contribute to overcoming the entropy reduction in the binding site or even exceeding it, leading to a favorable change in conformational entropy of binding.