Inflammatory processes in the brain require the cooperation of immunocompetent cells and glial cells, which communicate by secreting bidirectional mediators. Resident cells within the nervous system can synthesize and secrete inflammatory cytokines, as well as neuropeptides, contributing to the response within the CNS to injury or immunological challenge. Although the mechanisms of cell activation and immune interaction are poorly understood, accumulating evidence implicates these pathways in neuropathogenesis, as described here by Sharon Wahl and colleagues. For example, in the acquired immune deficiency syndrome (AIDS), HIV-1-induced nervous system dysfunction and dementia are associated with the presence of infiltrating leukocytes and the release of inflammatory cytokines. Defining the pathways of cytokine dysregulation and neurotoxicity invoked by the infiltrating leukocytes, as well as the contribution of the neural cells themselves, may help to identify mechanisms of intervention in this and other debilitating CNS diseases.