Abstract: Drug abuse represents a serious health issue worldwide resulting personal suffering, as well as social and economic burden. Drug abuse is considered the third killer in some western societies since it affects more and more people, compared with cerebral-cardiovascular disease or malignant cancer. China faces emerging epidemics of drug abuse as evidenced that drug abusers are on the rise in recent years. Despite the recognized impact of drug abuse on the brain reward system, mechanisms underlying the ability of drug abuse to initiate a cascade of neuroinflammatory response, which finally result in widespread neurotoxicity within the complex network of cell-to-cell interactions, have not yet been fully identified. Understanding the detailed mechanisms underlying neuropathological progression induced by drug abuse is thus the next logical step that is of paramount importance. The control and eradication of neurological complications associated with drug abuse continues to be an important goal toward improving the well-being of drug abusers. This review summarizes the potential role of Sigma receptor antagoinsts in drug abuse-mediated neuroinflammation and neurotoxicity, both of which comprise the hallmark features of drug abusers. These findings will set a stage for providing a new generation of novel therapeutic agents for drug abuse involving neuroinflammation and neurotoxicity.