Infection of the brain with human immunodeficiency virus 1 (HIV-1) often leads to the devastating loss of mental faculties. Surprisingly, HIV-1 elicits such brain dysfunction without significantly infecting neurons, astrocytes and oligodendroglia. The target for HIV-1 in the brain is the macrophage, which usually functions as a phagocytic, antigen-presenting and immune-regulatory cell. How can these cells produce such serious cognitive and motor brain impairments? Here, Hans Nottet and Howard Gendelman propose that HIV-1 penetrates the blood-brain barrier inside differentiating macrophages, which become immune activated once inside the brain, and secrete high levels of neurotoxins. Chronic, subclinical disease results by astrocyte regulation of macrophage effector functions. Ultimately, endogenous control mechanisms break down, leading to motor and mental impairments in some affected subjects.