Chameleonic behavior refers to the ability of a compound to modulate its polarity through conformational flexibility, such that in aqueous solution its polar groups are exposed to solvent, but in nonpolar environments alternative conformations are favored in which the polar groups are shielded from solvent by nearby bulky groups or through involvement in intramolecular hydrogen bonds. Conformational modulation of this kind enables compounds to expose sufficient polar surface to achieve acceptable aqueous solubility, while the ability to shield polar groups lowers the energetic cost of desolvating the molecule, reducing the energetic barrier to entering the lipid membrane. Evidence suggests that macrocycles are particularly well suited to exemplify chameleonic properties, compared to acyclic compounds of similar MW, likely because the reduced number of conformational states available to macrocycles decreases the entropic cost of interconverting between the distinct conformational ensembles that predominate in the two different solvent environments.