The paraoxonase gene family contains at least three members, including PON1, PON2 and PON3, which are located on chromosome 7q21.3-22.1. Until recently, there has been little insight into the role of the respective gene products in human physiology and pathology. However, emerging evidence from biochemical and genetic experiments is providing clues about the role(s) of the products of these genes. For example, the PON1 gene product is serum paraoxonase, which is expressed mainly in the liver and which hydrolyzes organophosphates. Serum paraoxonase circulates on a subfraction of high-density lipoproteins and appears to use phospholipids on both low and high-density lipoprotein particles as a physiological substrate. This functional relationship could explain the reported associations between common variation in the PON1 gene and phenotypes related to atherosclerosis and lipoprotein metabolism. In contrast, the PON2 mRNA is expressed ubiquitously, and to date there are no mechanistic experiments that yield insights into its physiological role. However, there have been reports of association between common variation in PON2 and some metabolic quantitative phenotypes, such as plasma lipoproteins, plasma glucose, birthweight and atherosclerosis. Such genetic associations could point to the possible physiological role(s) of PON2. At present, the role of the PON3 gene product is very poorly understood. Complementary lines of research should soon clarify whether there might be merit in clinical testing for genetic variation in the paraoxonase gene family or whether the gene products might be good candidates for therapeutic interventions.