Dependence continues to be an unsolvable problem. Now, some people become dependent or abuse psychoactive substances as a recreational activity. Many think they can give up any time but many progress to dependence. Although the brain is an immune-privileged organ recent studies suggest neuroinflammation can alter brain function. The focus of this review article is discussing a different aspect of the immune system in drug dependence. Also, the adverse effect of substance abuse on the immune system and the possible outcome is investigated.