Spanning three decades in research, Paraoxonases (PON1) carried potential of dealing with neurotoxicity of organophosphates entering the circulation and preventing cholinergic crisis. In the past few years, the Paraoxonase multigene family () has been shown to play an important role in pathogenesis of cardiovascular disorders including coronary artery disease (CAD). The genes are clustered in tandem on the long arm of human chromosome 7 (q21, 22). All of them have been shown to act as antioxidants. Of them, PON3 is the least studied member as its exact physiological substrate is still not clear. This has further led to limitation in our understanding of its role in pathogenesis of CAD and development of the potential therapeutic agents which might modulate its activity, expression in circulation and tissues. In the present review, we discuss the structure and activity of human PON3 enzyme and its Single nucleotide variants that could potentially lead to new clinical strategies in prevention and treatment of CAD.