The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small molecule CNS drugs is characterized by a high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies and in silico models have been reported to improve BBB penetration, none were developed to predict Kp,uu directly. We describe a physics-based computational approach, solvation free energy calculations (energy of solvation or E-sol), to predict Kp,uu. Prospective application of this method to internal CNS drug discovery programs highlighted the utility and accuracy of this new method, which showed a categorical accuracy of 79% and a R2 of 0.61 from a linear regression model.