The purpose of this study is to describe the interrelationship between nitric oxide (NO) and nicotine in cigarette smoking addiction, in view of the underlying hypothesis that NO contributes to smoking (nicotine) addiction, and to suggest the ways to improve prevention as well as cessation strategies. A literature search of Medline using the keywords nicotine and nitric oxide covering 1995 to May 2001 was made. Further information not obtained from the Medline search was derived from the references cited in these publications. Smokers are exposed first to high concentrations of inhaled NO from smoke and, second, to endogenously released NO after uptake of nicotine into the brain. As a result, the basal endogenous NO synthesis in airways and blood vessels of smokers is reduced. Subsequently, because NO is involved in maintaining airway dilatation, smokers may have constricted airways. During smoking, however, NO from smoke may dilate the constricted airways, allowing the smoke an easier passage into the lungs, and exposing the body and the brain to more nicotine. NO can endogenously be released by nicotine from nervous tissue, and may decrease the sympathetic output of the brain, which is associated with stress reduction. This second form of exposure to NO also inhibits the re-uptake of dopamine, which may contribute to dopaminergic receptor stimulation and thus to the acute rewarding effects of nicotine. The important role of NO in nicotine addiction is further supported by the finding that in animals NO synthase (NOS) inhibitors attenuate symptoms of the nicotine abstinence syndrome. NO may contribute to the development of cigarette smoking and nicotine addiction since: (1) inhaled NO from smoke may be able to increase nicotine absorption, (2) NO released through nicotine reduces symptoms of stress, (3) NO endogenously released by nicotine increases post-synaptic dopamine levels, and (4) NOS inhibitors attenuate symptoms of the nicotine abstinence syndrome. It remains to be determined whether reducing the NO content in cigarette smoke may reduce nicotine absorption. It also needs to be clarified whether NOS inhibitors or a low L-arginine diet might be useful in the treatment of nicotine addiction.