A major-if not the major-rationale for the study of carbohydrate chemistry derives from the roles played by glycoconjugates in biology [l]. In almost all such roles a carbohydrate ligand must bind to a protein receptor. There exists, then, tremendous potential to modulate biological activity through the creation of high affinity mimics of native saccharide receptors; such compounds have potential therapeutic value in the treatment of viral, parasitic, mycoplasmal and bacterial infections, and the treatment of a range of human cancers [ 2 ] . The study of proteincarbohydrate interaction, then, forms a key focus of this discipline of carbohydrate chemistry and biology.The development of inhibitors of carbohydrate-mediated biological recognition is impeded by the exceptionally weak bindings that typify protein-carbohydrate interaction [ 3 ] . In this chapter we consider the energetic issues central to proteincarbohydrate interaction. We devote some space to a consideration of the general forces and interactions that provide both affinity and specificity during association in aqueous solution. A range of phenomena observed during protein-carbohydrate association appear to be dependent on the assay used to evaluate 'binding'; we therefore consider the some of the more commonly utilized assays of protein carbohydrate interaction and delineate the microscopic events each assay is designed to evaluate. Finally, the last ten years has seen tremendous activity in the development of multivalent carbohydrate ligands; we thus explore the energetic issues surrounding multivalency in ligand binding.Throughout, we endeavor to relate energetic issues directly to protein-carbohydrate interaction. We stress, however, that a tremendous body of literature pertaining to the very issues central to protein-carbohydrate interaction exists in the context of other binding systems. Where appropriate, we draw on the lessons and experience of these adjacent disciplines in our consideration of the biophysical aspects of protein-carbohydrate interaction.