Modern techniques in microcalorimetry allow us to measure directly the heat changes and associated thermodynamics for biomolecular processes in aqueous solution at reasonable concentrations. All these processes involve changes in solvation/hydration, and it is natural to assume that the heats for these processes should reflect, in some way, such changes in solvation. However, the interpretation of data is still somewhat ambiguous, since different non-covalent interactions may have similar thermodynamic signatures, and analysis is frustrated by large entropy-enthalpy compensation effects. Changes in heat capacity (Delta C(p)) have been related to changes in hydrophobic hydration and non-polar accessible surface areas, but more recent empirical and theoretical work has shown how this need not always be the case. Entropy-enthalpy compensation is a natural consequence of finite Delta C(p) values and, more generally, can arise as a result of quantum confinement effects, multiple weak interactions, and limited free energy windows, giving rise to thermodynamic homeostasis that may be of evolutionary and functional advantage. The new technique of pressure perturbation calorimetry (PPC) has enormous potential here as a means of probing solvation-related volumetric changes in biomolecules at modest pressures, as illustrated with preliminary data for a simple protein-inhibitor complex.