Changes in water structure are substantiated as the major source of enthalpy-entropy compensation that is observed for predominantly hydrophobic or electrostatic protein-ligand interactions. Although the protein conformational perturbations detected by NMR procedures must also elicit entropic and enthalpic contributions to ΔG°, the observation of extreme enthalpy-entropy compensation (near-constancy of ΔG°) for many experimental protein-ligand systems signifies a relatively minor role for those contributions. Because the entropy increase occurring in hydrophobic and electrostatic interactions reflects the adoption of a less-ordered structure by water, the weakening of hydrogen bonds to achieve that more random solvent state necessarily gives rise to a compensatory enthalpy decrease. Despite initial reluctance on the part of many researchers to regard the solvent as part of the thermodynamic system, the role of water as a modulator of reaction energetics in biological interactions seems to be slowly but surely gaining ground.