The journey to find genes responsible for determining sensitivity or resistance to specific insecticides led to the paraoxonase (PON1) gene on human chromosome 7. This gene encodes a 355 amino acid protein that is localized on the high density lipoprotein (HDL) particles in plasma. Characterization of this gene revealed that different individuals expressed both different forms of this enzyme with amino acid substitutions at positions 55 and 192 as well as different levels of this protein. Additional studies showed that mutations in the regulatory region of the PON1 gene contributed to the very different levels of plasma PON1 among individuals. It turned out that both the level of the enzyme as well as the amino acid present at position 192 (glutamine or arginine) are important in determining resistance to the active forms of specific organophosphorus insecticides, especially diazinon and chlorpyrifos. The position 192 amino acid also determined whether an individual’s plasma hydrolyzed the nerve agents soman and sarin at high or low rates. It is not yet known whether these different rates of hydrolysis observed in biochemical assays reflects differences in sensitivity of individuals to nerve agents. Taken together, the experiments carried out indicate that engineered recombinant PON1 is an excellent candidate to use for treating cases of poisoning by specific organophosphorus compounds. The available data on the relationship of PON1 levels and position 192 genotype led us to introduce the term PON1 status to describe an individual’s PON1 plasma level as well as their position 192 genotype. The characterization of the genetic variations of the PON1 gene together with experiments showing that HDL can protect the lipids in low density lipoprotein particles (LDL) from oxidation and that it was PON1 that was responsible for this protection have opened an entirely new area of investigation, the role of PON1 in protecting against vascular disease. More recent reports have noted that PON1 also metabolizes a number of drugs, activating some and inactivating others. It is the purpose of this book to describe the advances in understanding the role of PON1 in both cardiovascular disease and toxicology of insecticide exposure as well as describe some of the recent information indicating an important possible role in the pharmacokinetics of drug metabolism. The final chapter of the book provides an overview of the areas of PON1 research and suggests future directions for research on PON1 as well as the related, linked genes PON2 and PON3.