Drug addiction is a chronic disease with biological, psychological and social consequences that includes three stages of drug use, withdrawal and relapse. The relapse is considered as the main obstacle to the treatment of addiction. In spite of extensive researches on neurobiological mechanisms of relapse using a variety of chemical and electrical methods, the rate of relapse to drug use is 40– 60 percent within a year after the cessation of treatment and it has remained unchanged for the half a century ago. On the other hand, most studies in the field of addiction have been performed on laboratory animal models that results cannot be translated into clinical studies precisely, however, most available treatments are still relatively ineffective, because little information is available on the molecular and cellular underlying mechanisms of relapse. Therefore, given the importance of recognizing of relapse, in this review article we evaluate physiologically this phenomenon from various aspects, including the animal models, cellular-molecular mechanisms, predisposing factors, biomarkers, chemical, electrical, cognitive behavioral and Iranian traditional medicine treatment approaches, in the hope that researches on addiction treatment should be evaluated more purposefully than before.