Paraoxonases are a group of enzymes with a high "substrate-promiscuity", being able to act on many structurally different compounds. To date, there is no consensus regarding the physiological substrate(s) of these enzymes. Recent data suggest that the N-acyl homoserine lactones (AHLs) produced by different Gram-negative bacteria, including the opportunistic Pseudomonas aeruginosa, could be such substrates. Due to the ability of paraoxonases to hydrolyze AHLs, they represent an alternative mechanism of protection against pathogen microorganisms, interfering with the quorum sensing systems that allow these bacteria to respond in a coordinate manner to different changes in the extracellular environment. This mini-review presents some novel aspects regarding the relationship between paraoxonases and the aforementioned compounds, highlighting the potential role of these enzymes as a component of the humoral innate defence system.