The pathobiology of dementia that accompanies infection with the human immunodeficiency virus involves complex interactions of the virus with the host. The virus enters the brain either as free viral particles or hidden in infected monocytes (the "Trojan Horse" mechanism). Within the brain it infects microglial cells, causing a productive and cytopathic infection, and infects astrocytes, causing a latent or restricted infection. The brain thus acts as an important reservoir for the virus. These infected cells release several viral proteins, some of which are toxic to neurons and are called "virotoxins." These virotoxins activate glial cells to release a number of soluble factors that are either toxic to neurons or cause chemotaxis of monocytes into the brain. Because the glial cells outnumber the neurons by 10:1, this is an important mechanism by which the virotoxins amplify their toxic potential and initiate a self-perpetuating cascade of events, resulting in a "domino effect" on the brain. Only a transient exposure to virotoxins is necessary to initiate these positive feedback loops. Thus, a "hit and run" phenomenon may be operative within the brain. Therapeutic approaches are based on decreasing the viral burden in the brain and blocking the actions of the key neurotoxic substances at various levels within the various cascades.