In recent years, emphasis and attention have been focused on the use of medical ozone (O3). Despite its huge diffusion, certain confusion still persists concerning its potential toxicity as a strong oxidant. Although its use as safety remedy in the medical field has been described since the last century, this confusion still represents a major factor preventing its full acceptance. Furthermore, the use of ozone therapy (OT) in specialities so different like neurology, orthopaedics, internal medicine, sports medicine, dermatology, endocrinology and others makes difficult the collocation of OT as a single specialist branch. In this context, the apparent heterogeneous network of diseases in which OT seems to be active resembles those proposed for the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. This fact, extremely exciting by a pure pharmacological point of view, may cause conflict between the different fields of application and the various medical areas. To our opinion, with the aim to explore the complexity of the OT therapeutic activity in the medical field newly clinical protocols must be designed.