The interactions between the immune and nervous systems are very complex, and yet our understanding of these interactions is still relatively limited. The neuroinflammatory reaction that can accompany HIV infection occurs because of a cascade of events that appears to require the migration of HIV-infected cells across the blood-brain barrier. In susceptible individuals, this leads to inflammatory processes which can include substantial changes in neuronal function. It is possible to consider the inflammatory events to be composed of two essential processes. The first process is cellular traffic, and the second, is the expression and recognition of the various pro-inflammatory and/or toxic mediators. The added complication of drug abuse adds complexity to the traffic and mediator release events, and depending on the specific drug being abused, the disease can be exacerbated in these individuals. An understanding of the fine details of these mediator and traffic processes should provide useful targets for therapeutic intervention to attenuate disease associated with HIV infection.