How cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CB1 is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoietic colony formation in which cannabinoids have demonstrated a clear role as important modulators.