Monte Carlo (MC) statistical mechanics simulations have been carried out for more than 200 organic solutes, including 125 drugs and related heterocycles, in aqueous solution. The calculations were highly automated and used the OPLS-AA force field augmented with CM1P partial charges. Configurationally averaged results were obtained for a variety of physically significant quantities including the solute-water Coulomb and Lennard-Jones interaction energies, solvent-accessible surface area (SASA), and numbers of donor and acceptor hydrogen bonds. Correlations were then obtained between these descriptors and gas to liquid free energies of solvation in hexadecane, octanol, and water and octanol/water partition coefficients. Linear regressions with three or four descriptors yielded fits with correlation coefficients, r(2), of 0.9 in all cases. The regression equation for log P(octanol/water) only needs four descriptors to provide an rms error of 0.55 for 200 diverse compounds, which is competitive with the best fragment methods. For water, the expanded data set of 85 solutes and improved statistical analyses bring into question the significance of the Lennard-Jones and surface area terms that have been featured in prior linear-response treatments. The results are sensitive to the choice of partial charges for the solute atoms; poor representation of some functional groups can lead to the need for specific corrections in the regression equations. This is expected to also be true for force-field-based scoring functions for protein-ligand binding. In all cases, the present descriptors that emerge as most significant sensibly reveal the key physical factors that control solvation, especially solute size in organic solvents and electrostatic interactions in water. Furthermore, additional MC simulations for solutes in both water and ethanol clearly demonstrate that the key differential between water and alcohols is the greater hydrogren-bond-donating ability of water, which explains the significance of a solute's hydrogen-bond-accepting; ability for log P(octanol/water).