Computational tools utilizing a unique empirical modeling system based on the hydrophobic effect and the measurement of logP(o/w) (the partition coefficient for solvent transfer between 1-octanol and water) are described. The associated force field, Hydropathic INTeractions (HINT), contains much rich information about non-covalent interactions in the biological environment because of its basis in an experiment that measures interactions in solution. HINT is shown to be the core of an evolving virtual screening system that is capable of taking into account a number of factors often ignored such as entropy, effects of solvent molecules at the active site, and the ionization states of acidic and basic residues and ligand functional groups. The outline of a comprehensive modeling system for virtual screening that incorporates these features is described. In addition, a detailed description of the Computational Titration algorithm is provided. As an example, three complexes of dihydrofolate reductase (DHFR) are analyzed with our system and these results are compared with the experimental free energies of binding.