Paraoxonase (PON1) is a Ca2+-dependent enzyme whose mechanism of action is incompletely elucidated. PON1 was originally found to be responsible for the hydrolysis of paraoxon, a catabolite of the insecticide parathion, but this enzyme is equally able to hydrolyze other substrates such as phenyl acetate. PON1 exhibits two sequence polymorphisms, Arg-->Gln 192 and Met-->Leu 55, respectively, of which the former is responsible for the distinct catalytic activity of the two corresponding allozymes against paraoxon. The PON1 gene is a member of a family of at least three related genes. Although the physiologic substrate of PON1 is unknown, a protective role against the oxidative degradation of serum lipoproteins has been attributed to this enzyme. Indeed, PON1 is a component of a spectrum of circulating high density lipoprotein particles and can hydrolyze oxidized phospholipids and cholesteryl ester hydroperoxides. Studies have been conducted to evaluate the possible "protective" role of PON, and especially the influence of the Arg-->Gln 192 polymorphism, in coronary artery disease. Results from these investigations are conflicting, and recent data suggest a complex pattern with influences from other polymorphisms in either the PON1 and/or the PON2 and PON3 genes, or even another region of the gene cluster. A number of related factors, which include the heterogeneity of the high density lipoprotein particles incorporating PON(s), the metabolism of associated apolipoproteins such as apoJ/clusterin, the respective roles of PON(s) and other high density lipoprotein-associated enzymes such as platelet-activating-factor acetyl-hydrolase and lecithin-cholesterol acyltransferase, modifications of high density lipoprotein composition and activity under acute-phase conditions, the dietary and environmental regulation of PON(s), and the actual in situ availability of PON in the atherosclerotic artery wall, must equally be taken into account.