This paper presents a hypothesis relating the exclusion of a molecule (solute) from the surface of a protein in aqueous solution with the ability of that molecule to render surfaces "protein-resistant", that is, resistant to the adsorption of proteins from aqueous buffer. While few current data test this hypothesis, it does suggest that surfaces presenting groups derived from certain osmolytes-molecules synthesized by cells to relieve osmotic stress-will be protein-resistant. These predictions were tested by constructing protein-resistant, self-assembled monolayers (SAMs) based on the osmolytes betaine and taurine. Examination of data from the literature also revealed that most of the known protein-resistant surfaces are based on displays of kosmotropes-molecules that stabilize the native structure of proteins. The connection between protein resistance, kosmotropicity, and biological function as an osmolyte may illuminate all three properties.