Mononuclear phagocytes (MP; bone marrow monocyte-derived macrophages, histiocytes, alveolar macrophages, Kupffer cells, perivascular macrophages, and microglia) function as sentry and surveillance cells by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. Interestingly, these same cells are reservoirs and vehicles of dissemination for the human immunodeficiency virus (HIV). How virus alters the MP immunoregulatory activities so it can complete its own life cycle and affect disease is only recently being unravelled. Physiologic, anatomic and functional changes also underlie virus-MP interactions and include multinucleated giant cell formation, changes in ion channel expression and cell volume, and robust secretory responses with the production of numerous secretory factors affecting tissue injury. The balance between such MP activities and ability to both mobilize an adaptive immune response to thwart viral growth underlies the progression of viral infection and clinical disease. This review serves to discuss the functions of MP in HIV disease by bringing together what is known with what remains unknown. The advent of functional genomics and proteomics has opened the ways to address the intricacies of viral-host interactions and has provided new avenues for therapeutic interventions and disease monitoring that takes advantage of specific intracellular relationships between the virus and its host cell.