Although ozone therapy has been used as an alternative medical approach for four decades, it is now possible to evaluate some mechanisms of action and possible toxicity. In contrast with the respiratory tract, human blood exposed to appropriate ozone concentrations is able to tame its strong oxidant properties and neither acute nor chronic side effects have ensued in millions of patients treated with ozonated autohaemotherapy. Many studies aimed at clarifying biological effects, defining any possible damage, the therapeutic window, and suitable doses able to express therapeutic activity. Although an unfashionable and unpopular approach, it is hoped that orthodox medicine will help to critically assess the validity of ozone therapy.