Background: Exposure to persistent organic pollutants (POPs) is linked to many chronic diseases, including diabetes and cardiovascular diseases. Among several possible mechanisms are gradual glutathione depletion and mitochondrial dysfunction after chronic exposure to very low doses of POP mixtures. However, it is biologically noteworthy that glutathione status and mitochondrial function is subject to hormesis, defined broadly as mild stress-induced stimulation of cellular protective mechanisms, including increased synthesis of glutathione and promotion of mitochondrial biogenesis. Although high levels of reactive oxygen/nitrogen species (ROS) can cause cellular damage, certain levels of ROS function as signalling molecules to induce hormetic effects. Thus, similar to many other stressors generating ROS, glutathione status and mitochondrial function can be improved at higher POP doses. However, higher POP levels are dangerous despite their hormetic effects due to other adverse phenomena. Also, the persistent nature of POPs can make hormetic effects less effective in humans as hormesis may be the most active with transient stressors. Hormesis-inducing stressors should be placed into three categories for public health purposes: (1) disadvantageous: chemicals like POPs and radiation, that could harm humans by endocrine disruption, action of chemical mixtures and susceptible populations; (2) neutral: cold, heat, and gravity; and (3) advantageous: moderate exercise, phytochemical intake, and calorie restriction. Noting that regulation of POPs, while critical, has provided insufficient protection because POPs persist in human bodies and the food chain, advantageous stressors should be used by the public to mitigate glutathione depletion and mitochondrial dysfunction due to POPs.