The enantioselectivity of cross-linked crystals of gamma-chymotrypsin in the transesterification of the medicinally important compound methyl 3-hydroxy-2-phenylpropionate (1) with propanol has been examined in a variety of organic solvents. The (k(cat)/K-M)(s)/k(cat)/K-M)(R) ratio in this enzymatic process can be forced to span a 20-fold range simply by switching from one solvent to another; in fact, while the enzyme strongly prefers the S-enantiomer of 1 in some solvents, the R-antipode is more reactive in others. These striking observations are quantitatively rationalized by accounting for the energetics of desolvation of S-1 and R-1 in the enzyme-bound transition states. In order to accomplish this, explicit rules have been established for the modeling and thermodynamic quantification of the partially desolvated substrate’s transition state moieties.