Management of serum low-density lipoprotein has been a cornerstone of cardiovascular medicine for the past two decades. More recently, the attention paid to the protective role of high-density lipoprotein (HDL) in atherosclerosis has increased substantially, particularly with respect to the antioxidant properties of HDL. Considerable evidence supports the notion that the paraoxonase gene family is largely responsible for the antioxidant properties of HDL. This article reviews the three known members of the paraoxonase family and the evidence that supports their likely role in the development and progression of atherosclerosis.