The contribution of physicochemical descriptors to lipophilicity, water solubility, and intestinal absorption and oral bioavailability in humans is considered. Partitioning in the octanol/water system is presented as a competition between two opposing effects: volume and hydrogen bond acceptor ability. Water solubilities of liquid compounds are roughly equal to their reciprocal logP values. However, there is also a detectable contribution of H-bond donor ability to water solubility. The main problem in predicting the solubilities of solid chemicals and drugs is the estimation of their crystal lattice energies. QSAR approaches that add terms such as melting point, and the product of H-bond donor and acceptor parameters are not sufficient to make these predictions practical. Human intestinal absorption for passively transported drugs is almost completely correlated with hydration processes that are determined by H-bond acceptor and donor abilities. It is emphasized that structural features of drug molecules have significant influences on their properties. Classic QSAR approaches are not enough to create stable, predictive models for diverse drugs. A combination of Similarity and QSAR approaches is one possibility to take all physicochemical properties in addition to structural features into account.