Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) are a persistent health problem worldwide. HIV-1 seems to enter the brain very soon after peripheral infection and can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction, and frank dementia. Infected peripheral immune-competent cells, in particular macrophages, appear to infiltrate the CNS and provoke a neuropathological response involving all cell types in the brain. The course of HIV-1 disease is strongly influenced by viral and host factors, such as the viral strain and the response of the host's immune system. In addition, HIV-1-dependent disease processes in the periphery have a substantial effect on the pathological changes in the central nervous system (CNS), although the brain eventually harbors a distinctive viral population of its own. In the CNS, HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes, and glutamate receptor-mediated excitotoxicity, all of which can initiate numerous downstream signaling pathways and disturb neuronal and glial function. Although there have been many major improvements in the control of viral infection in the periphery, an effective therapy for HIV-1-associated dementia (HAD) is still not available. This article addresses recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and discusses experimental and potentially future therapeutic approaches.