Human paraoxonase (PON) is a member of the gene family that includes PON1, PON2, and PON3. PON is known for its capacity to hydrolyze a wide range of substrates, including organophosphorus compounds, nerve gases, and aromatic carboxylic acid esters. Recent advances: Several studies have highlighted the involvement of PON, particularly PON1, in the modulation of the capacity of HDL to protect against the atherosclerosis process and its clinical manifestations. PON1 exhibits antioxidant and anti-inflammatory activities and may be involved in the regulation of the principal anti-atherogenic activity of HDL, that is, the regulation of the reverse cholesterol transport process.Although epidemiological studies have shown that there is an inverse relationship between HDL levels and cardiovascular risk, several studies have emphasized the importance of HDL functionality in protecting against cardiovascular diseases. Given that PON1 is involved in several atheroprotective functions of HDL, the aim of this paper is to review the existing literature on PON1 and to discuss the principal mechanisms by which PON1 may exert its different activities.The elucidation of the mechanisms by which PON1 modulates the functionality of HDL as well as the identification of the interventions that stimulate PON1 activity and/or increase its plasma concentration would make it possible to propose new strategies to prevent cardiovascular diseases.