Ozone therapy is widely used in many countries since many years. Recently, the increasing widespread of this complementary therapy has been accomplished by an increased number of basic and clinic papers published on international journals. This lecture will deal on the first approach by a pharmacological point of view in the aim to characterize the mechanisms activated at sub-cellular level by ozone when used for medical and beauty application at low graded doses. The first theory was based upon the fact that the exposure to low, non-toxic, ozone concentrations could increase the efficacy of the endogenous antioxidant system by increasing the production or the activity of some enzymes exerting a key role in the mitochondrial respiratory chain. Many of the basic mechanisms of the ozone action are now well outlined. In addition, the modulation of interleukins productions and of some biochemical pathways related to inflammation and pain, indicates the rationale of its use in many pathological conditions related to pain, inflammation and age disorders. We also discuss on the mode of action of ozone that, with an hormetic mechanism, appear to be more similar to xenobiotic stress model than a pure pharmacological action. Indeed, our recent work in vivo on patients treated with major autohemo therapy (MAH) demonstrated the increase of Nrf2 level (P