Summary. Proteins retain function when attached to some surfaces (e.g., the cell membrane) and yet very often unfold and inactivate on others (e.g., the artificial surfaces used in many technologies). Our understanding of why this is, however, has been hampered by a lack of quantitative methods by which we can measure the thermodynamics of biomolecule-surface interactions. That is, despite a large body of qualitative literature describing how adsorption alters protein structure, and a large number of empirical studies searching for adsorption-resistant surfaces, quantitative, experimentally testable insights into how and why proteins unfold on some surfaces and not others have proven elusive. In response, we have developed a new experimental approach for measuring the folding free energy of biomolecules site-specifically attached to well- defined, macroscopic surfaces (i.e., flat at the molecular length scale), including surfaces that closely mimic the cell membrane. Comparison with bulk-solution-phase free energies then informs on the thermodynamics of the biomolecule's interactions with the surface and, in turn, the mechanisms that drive them. Using this novel approach we have, for the first time, accurately measured the free energy with which a simple biomolecule interacts with a set of chemically distinct macroscopic surfaces. In parallel, we have also developed both first- principles theory and atomistic simulation approaches that provide molecular-level structural details unavailable to experiment alone. Leveraging these promising preliminary results we propose here the systematic experimental, theoretical and computational study of protein-surface interactions, with our overarching goal being to understand protein-surface interactions in sufficient detail to predict or even rationally design protein-surface pairings supporting reversible refolding and the retention of function.