Free fatty acids, natural uncouplers of oxidative phosphorylation, are shown to differ from artificial ones in that they fail to increase conductance of phospholipid bilayers which are permeable for the protonated form of fatty acids but impermeable for their anionic form. Recent studies have revealed that uncoupling by fatty acids in mitochondria is mediated by the ATP/ADP antiporter and, in brown fat, by thermogenin which is structurally very similar to the antiporter. It is suggested that both the ATP/ADP antiporter and thermogenin facilitate translocation of the fatty anions through the mitochondrial membrane.