The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic "fields" is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformationally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface.