The empirically calculated parameter LogP(o/w), the log(10) of the coefficient for solvent partitioning between 1-octanol and water, has been used to provide the key data for a unique non-covalent interaction force field called HINT (Hydropathic INTeractions). This experimentally-derived force field encodes entropic as well as enthalpic information and also includes some representation of solvation and desolvation energetics in biomolecular associations. The theoretical basis for the HINT model is discussed. This review includes: 1) discussion of calculational representation of the hydrophobic effect, 2) the rationale for describing the experimental LogP(o/w) based descriptors used in the HINT force field and model as free energy-like, 3) the relationship between hydrophobic fragment constants and partial group electrostatic charge, and 4) the implications of structurally-conserved water molecules on free energy of molecular association. Several recent applications of HINT in structure-based and ligand-based drug discovery are reviewed. Finally, future directions in the HINT model development are proposed.