This book provides a systematic treatment of the thermodynamic theory of site-specific effects in biological macromolecules. It describes the phenomenological and conceptual bases required to allow a mechanistic understanding of these effects from analysis of experimental data. The thermodynamic theory also results in novel experimental strategies that enable the derivation of information on local, site-specific properties of a macromolecular system from analysis of perturbed global properties. The treatment focuses on binding phenomena, but is amenable to extension to the analysis of other cooperative processes, such as folding and helixSHcoil transitions. It covers a subject that bridges the gap between thermodynamics and the experimental analysis of the molecular basis of cooperativity in biological macromolecules and will be of interest to biochemists and biophysicists.