Oxidative Stress, deriving from a perturbation of the cellular balance between pro-oxidant and anti-oxidant molecules, has been involved in the patho-physiology of multiple diseases, and anti-oxidant supplementation are largely studied for therapeutic purposes. The Cannabis sativa derivates, the cannabinoids (CBs), are widely used as a recreational drug, but pharmacological activities also prompt to therapeutic use. Exposure to CBs rises physical and psychic effects which can evolve in both short-term and long-term toxicity. High inter-individual variation exists in the susceptibility to these effects. Many evidences show a complex modulator action of CBs on cellular oxidative stress, with different outcomes according to cellular type, microenvironment, time and dose of exposition. The subtle balance between anti-oxidant or pro-oxidant action of CBs should be taken into account to achieve a more accurate comprehension of the molecular mechanisms involved in toxicity, considering that OS is not merely a damaging factor, but is also involved in protective pathways.