Human atherosclerotic lesions contain a variety of lipids and oxidized lipids, which can induce atherogenic properties such as macrophage oxidation, lipoprotein oxidation and inhibition of cholesterol efflux from macrophages. These atherogenic properties of the plaque's lipid fraction are associated with the inhibition of paraoxonase 1 (PON1) lactonase activity. In contrast, incubation of PON1 with the plaque's lipid fraction reduces the lesion's atherogenic properties by lowering the capacity of the oxidized lipids to induce further oxidation. The mechanism of PON1's protective action and its endogenous substrate however remain elusive. Modeling studies may characterize PON1's possible active site, and help envisage the structure of potential endogenous and exogenous lactones as PON1 ligands. Such modeling thus may lead to a better understanding of PON1's anti-atherogenic mechanism of action.