The structure of a protein is strongly influenced by solvation. In the present review, the solvation effect is treated within the framework of statistical thermodynamics. The key quantity is the solvation free energy of protein and a fast method for its computation with explicit solvent is introduced. The applications of the method to the structural fluctuation of protein in water, structure determination of protein–protein complex, and urea effect on protein structure are then described, and the roles of solvent water and cosolvent are discussed from the standpoint of energetics.