Lipid bilayer membranes are the fundamental structure of biological membranes and are responsive to environmental changes such as temperature, pressure and concentrations of other components. Changes in the environment give rise to structural changes in the lipid bilayer membranes called phase transitions. In particular, the effect of membrane-active substances (i.e, ligands) on the phase transitions of lipid bilayer membranes varies significantly depending on the kinds of ligands. This is closely related to the affinities of ligands to the various phases of the bilayer membranes. In this review, the effect of representative ligands, long-chain fatty acids and inhalation anesthetics, on the lipid bilayer membrane under atmospheric and high pressure is described and the differences in ligand affinity to the bilayer membrane are explained thermodynamically.