This short review focuses on the role of central nervous system (CNS) perivascular macrophages as targets of productive infection of the CNS. Data discussed include the importance of these cells as early targets of infection and their productive infection with AIDS. Many of the immune molecules on perivascular macrophages are also found on subsets of blood monocyte/macrophages, some of which are expanded during human immunodeficiency virus (HIV) infection. These observations paired with the known bone marrow (BM) origin of perivascular macrophages and the BM as a site of HIV infection underscore the importance of the study of monocyte populations in the BM and blood, which are activated and infected as a source of virus that enters the CNS. Data presented and discussed herein suggest a role of HIV-infected BM-derived monocytes as "Trojan horse" cells that traffic to the CNS to become perivascular macrophages. The study of such cells including their timing of infection, activation, and traffic and the role of HIV-specific immune responses controlling their accumulation in the CNS warrant study with regard to CNS neuropathogenesis.