The antioxidant activity of HDL is largely due to the paraoxonase (PON1) located on it. Experiments with transgenic PON1 knock-out mice indicate the potential for PON1 to protect against atherogenesis. This effect of HDL in decreasing LDL lipid peroxidation is maintained for longer than that of antioxidant vitamins and could thus be more protective. Several important advances in the field of PON research have occurred recently, not least the discovery that two other members of the PON gene family PON2 and PON3 may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of PON1 and the discovery of possible modulators of its activity. Decreased coronary heart disease (CHD) risk associated with polymorphisms of PON1 which are most active in lipid peroxide hydrolysis revealed by meta-analysis is likely to be an underestimate of the true contribution of PON1 to CHD because these polymorphisms explain only a small component of the variation in PON1 activity. However, it is a very important observation because genetic influences are not likely to be confounded by other factors linked with both CHD and diminished PON1 activity. PON1 is extensively researched and strategies will hopefully emerge to increase its activity and provide a more satisfactory test of the antioxidant hypothesis of atherosclerosis than antioxidant vitamins have done.