The stability of proteins is affected by a variety of solvent additives. Sugars, certain amino acids and salts, and polyhydric alcohols stabilize proteins in solution and during freeze-thawing. Urea and guanidine hydrochloride destabilize proteins under either condition. These effects can be explained from the preferential interactions of the cosolvents with the proteins; i.e., the protein stabilizers are preferentially excluded from the proteins, while the destabilizers bind to them. There is a class of compounds, such as polyethylene glycol and 2-methyl-2,4-pentanediol, that destabilize proteins at high temperature but stabilize them during freeze-thawing. Such effects can be accounted for by their preferential exclusion from the native proteins determined at room temperature and from their hydrophobic character, which depends on temperature. During freeze-drying, only a few sugars appear to be effective in protecting proteins from inactivation, as most other stabilizers cannot exert their action on proteins without water. The stabilization is due to hydrogen bonding between the sugars and the dried proteins, the sugars acting as water substitute. Understanding the mechanism of the effects of solvent additives on the protein stability should aid in the development of a suitable formulation for protein.