Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) are often associated with severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. HIV-1-infected peripheral immune cells, in particular macrophages, appear to infiltrate the CNS, release neurotoxins and provoke a neuropathological response involving all cell types in the brain. In the CNS, HIV-1 and its components initiate activation of chemokine receptors, inflammatory mediators and glutamate receptor-mediated excitotoxicity, all of which can activate numerous downstream signaling pathways and disturb neuronal and glial function. Recent experimental evidence suggests that disturbance by HIV-1 results not only in neuronal injury and death but also in impairment of neurogenesis. This article will review recently identified pathological mechanisms which potentially contribute to the development of neurocognitive impairment and dementia in association with HIV-1 infection.