Abstract Efficient, reliable methods for calculating the binding affinities of noncovalent complexes would allow advances in a variety of areas such as drug discovery and separation science. We have recently described a method that accommodates significant physical detail while remaining fast enough for use in molecular design. This approach uses the predominant states method to compute free energies, an empirical force field, and an implicit solvation model based upon continuum electrostatics. We review applications of this method to systems ranging from small molecules to protein-ligand complexes.