A new molecular-modeling methodology has been applied to explain enzymatic enantioselectivity in water. This methodology, which combines vacuum molecular mechanics and the continuum solvation method, should provide a more realistic view of the solvent-enzyme and solvent-substrate interactions than the heretofore used approaches involving the vacuum molecular mechanics only. The methodology described herein has been validated using the experimental data on alpha-chymotrypsin＇s enantioselectivity in the hydrolysis of four chiral substrates. The reasons why the vacuum molecular mechanics, although not taking hydration into account, still in most cases provide a satisfactory approximation of reality are discussed.