In 1991, a revision of the terminology was made by the American Academy of Neurology AIDS Task Force, which developed the term human immunodeficiency virus (HIV)-1-associated cognitive motor complex (HIV-CMC), to encompass both the milder HIV-1- associated minor cognitive motor disorder (HIV-MCMD) and the more severe HIV-1-associated dementia complex (HIV-DC) (American Academy of Neurology AIDS Task Force, 1991). Although the advent of highly active antiretroviral therapies (HAART) has made great strides in extending life for AIDS patients, this longer life span may present increasing opportunity for HIV dementia (or HAD) to develop. HIV-1 encephalitis, the histo- and neuropathological correlate of central nervous system (CNS) HIV infection and HAD, occurs in most but not all cases of HAD. Infiltration of infected and/or activated immune cells from the periphery is increased with HIV infection and likely to be essential for development of HAD. Passage of infected cells or virus across the blood-brain barrier (BBB) results in the presence of activated immune cells in the brain, primarily macrophages and microglia but also astrocytes, which are thought to be directly causal to developing HAD. Continuous exposure to these noxious molecules is not necessary for progressive neuronal dysfunction and death. As a consequence of these generalized pathogenic mechanisms, numerous molecules and signaling pathways are secreted and activated that are thought to be involved in precipitating the pathophysiology of HAD, many of which share functions in both normal cellular signaling and other neurodegenerative diseases.