The disinfectant activity of ozone is well recognized and ozone is used worldwide for sterilization of water. The use of ozone as a complementary medical approach is less known, because it has mostly been used in an empirical fashion without a rational basis and appropriate controls. In spite of this drawback, the use of judicious and standardized ozone dosages can elicit the formation of ROS acting as natural physiological activators of several biological functions. There is now a reasonable understanding of a few mechanisms of action and, using classical pharmacological concepts, it appears possible to formulate a rationale for optimizing clinical applications. A further exciting development is that ozone, being an oxidizer, can upregulate the intracellular anti-oxidant enzymes eventually inhibiting the constant, life-long oxidative stress responsible for degenerative diseases and aging. Among various routes for the administration of ozone, the autohemotransfusion procedure, consisting in exposing blood to ozone, i.e. to a calculated and brief oxidative stress, appears safe, simple, inexpensive and amenable to be adjusted to different pathological states It is hoped that this review will help to dispel prejudices, to clarify that ozone toxicity can be tamed, to show that ozone can act as a bioregulator and to encourage controlled clinical investigations to evaluate definitely the validity of ozonetherapy.