Compound lipophilicity is of key importance to P450 binding affinity and enzyme selectivity. Here, lipophilicity is discussed with reference to the human drug-metabolizing P450 enzymes of families CYP1, CYP2 and CYP3. From an extensive compilation of log P values for P450 substrates, and by analysis of relationships between partitioning energy and substrate-binding free energy, the relevance of lipophilicity and other factors pertaining to P450 binding affinity is explained, leading to the formulation of lipophilicity relationships within substrates of each human P450 enzyme involved in drug metabolism. Furthermore, log P values for P450 substrates appear to represent markers for enzyme selectivity. Together with the important roles of hydrogen bonding and pi-pi stacking interaction energies, the desolvation of the P450 active site makes a major contribution to the overall substrate-binding energy and, consequently, a good agreement with experimental information is reported based on this analysis.