Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) is commonly associated with a multinucleated giant cell (MNGC) encephalitis termed HIV encephalitis (HIVE). Importantly, it occurs in most, but not all, cases of dementia related to HIV-1 infection. This chapter strives to describe what is known about multinuclear phagocytes (MP) activation and neuronal dysfunction with a focus on chemokines. Mounting evidence suggests that chemokines affect the pathogenesis of HAND. First, there is a state of “immune privilege” within the central nervous system (CNS) that is, in part, an evolutionary adaptation for which increasing evidence suggests that functional immunity is quite operative in the brain. Second, the maintenance of nervous system function requires protection from a variety of environmental insults occurring during inflammatory activities, such as HIVE. Third, chemokines (chemotactic cytokines) and chemokine receptors are an important part of the immune response that affects cell migration, activation, and tissue homeostasis. Fourth, following local production, chemokines induce leukocyte cytoskeletal changes, for example, actin polymerization, optimizing cell migration to areas of microbial infection or degeneration. Chemokine receptors are critical for the infection of perivascular macrophages and microglia. It has also been shown that chemokines and their receptors play a more direct role in the neuropathogenesis of HIV-1 infection. The neuropathogenesis of HIV-1 infection revolves around inflammatory factors secreted from virus-infected and immunocompetent brain MP. Chemokines and their chemokine receptors are expressed in the nervous system, and their engagement affects neuronal and glial function.