INTRODUCTION. The central nervous system (CNS) has traditionally been regarded as an immunologically privileged and isolated organ. This immunoisolation is achieved through the specific structure of the blood brain barrier and CNS immunosuppressive microenvironment. 1,2 However, activated macrophage/microglia (MO) and astrocytes participate in the pathogenesis of various neurological diseases through expressing of MHC and adhesion molecules and releasing reactive oxygen intermediates, quinolinic acid, chemokines, cytokines, and other components of inflammation. The role of macroglia/macrophages and astrocytes in cellular/molecular mechanisms of pathogenesis of three common dementias; HIV-associated dementia (HAD), Alzheimer’s disease (AD), and multiple sclerosis (MS) have been studied. Each disease had its specific clinical course and symptomatology that are well known. At the cellular and molecular levels there are both common and distinct features that are under study and require further elucidation. Recently Link et al. 3 indicated support for roles of both microglia and astrocytes in regulating demyelination in MS. We have generalized this significant concept of neuropathogenesis to HAD and AD. HIV-1 infection is the original insult in Neuro-AIDS. In fact, our results indicate that there are neurovirulent strains of HIV-1 that invade the brain. Furthermore, we have published preliminary studies showing that there is brain regional heterogeneity of macrophage/microglia, virus load, and virus strains. At the cellular level, there is a greater virus load in central nervous system (CNS) macrophage/microglia than in peripheral nervous system (PNS) macrophages. In both tissues, macrophages appear to be involved in pathogenesis and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). Furthermore, we have demonstrated increased NO synthase in brain interneurons of drug abusers with AIDS associated with increased neuronal death (manuscript under review). The etiologies of AD and MS remain unknown. However, cellular/molecular mechanisms of pathogenesis are specific manifestations of these diseases. For example, it is clear that AD results from production of aberrant eta-amyloid proteins and oligopeptides. Microglia and astrocytes are activated as a result and are associated with further damage. Demyelination in MS involves lipid-laden macrophages perhaps spurred by viral and other antigens. In all three diseases cytokine/chemokine communication between microglia and astrocytes occur and apoptosis is a mechanism of neuronal death. Also, apoptosis of oligodendrocytes occurs in MS.