The paraoxonase (PON) gene cluster contains at least three members, including PON1, PON2, and PON3, located on chromosome 7q21.3-22.1. Until now 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, which indicates that PON(s) acts as important guardians against cellular damage from toxic agents, such as organophosphates, oxidized lipids in the plasma low-density lipoproteins. In parallel, substantial data have been published on the association between the polymorphisms of PON(s) and coronary heart disease. It has become clear that the polymorphisms significantly affect the prevalence of coronary heart disease. However, the associations between the PON(s) polymorphisms and most of these conditions were found to be inconsistent when additional populations were investigated. This contribution provides an overview of the status of research of each of the three genes and the available association studies and the potential problems in interpreting the data. We also review the current evidence on the association between PON(s) polymorphisms and diseases other than coronary heart disease and some metabolic quantitative phenotypes, such as plasma lipoproteins, plasma glucose, and birthweight. Finally, we suggest directions for the future that might elucidate the role of the PON genetic polymorphisms in this potentially important function of PON(s) and the role in coronary heart disease and other related diseases.