Infection with the human immunodeficiency virus-1 (HIV-1) can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. After infiltrating peripheral immune competent cells, in particular macrophages, HIV-1 provokes a neuropathological response involving all cell types in the brain. HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways and disrupt neuronal and glial function. This review will discuss recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and potential approaches for development of future therapeutic intervention.