Organophosphorus (OP) compounds are still among the most widely used insecticides, and their main mechanism of acute toxicity is associated with inhibition of acetylcholinesterase. Measurements of urine metabolites and of blood cholinesterase activity are established biomarkers of exposure to OPs and of early biological effects. In recent years, increasing attention has been given to biomarkers of susceptibility to OP toxicity. Here we discuss the polymorphisms of paraoxonase (PON1), a liver and serum enzyme that hydrolyzes a number of OP compounds, and its role in modulating the toxicity of OPs. We stress the importance of determining PON1 status, which encompasses the PON1192Q/R polymorphism (that affects catalytic ability toward different substrates) and PON1 levels (which are modulated in part by a C-108T polymorphism) over straight genotyping. Epidemiological studies on OP-exposed workers that include assessment of PON1 status to validate in human populations the role of PON1 as a determinant of susceptibility to OPs, as indicated by animal studies, are needed. Documentation of exposure and of early health effects would be most relevant to increase the predictive value of the test.