HIV-mediated CNS damage is a result of a combination of direct invasion of the brain by the virus and chronic immune activation leading to in situ cerebral inflammatory reactions. This can manifest clinically as chronic cognitive and/or motor impairment, and given the delicate balance of the CNS milieu, it can result in compartmentalized infection or reservoir establishment, or both. The interactions among the virus, the host immune system, and the cells of the CNS, together with effects on host metabolism, are detailed in this chapter. The implications this has on clinically overt neurological dysfunction and the effects of antiretroviral therapy are also described.