Macrophages in brain, lung, and lymphatics constitute a major HIV reservoir during subclinical infection and disease. During HIV transmission macrophages are seemingly one of the first cells infected, being as efficient as T cells in supporting productive viral replication. Macrophages control a myriad of cell-mediated immune responses that regulate the levels of infection and lead to viral persistence. HIV determinants control viral entry and productive replication and, taken together with cellular differentiation factors, decide the outcome of virus-macrophage interactions. Most important, many clinical manifestations of HIV infection such as encephalitis, myelopathy, pneumonitis, and lymphadenopathy are closely linked to viral replication. Indeed, tissue pathology often correlates with viral gene expression in tissue macrophages. Taken together, these observations provide strong support for a central role of macrophages in progressive HIV infection and its clinical manifestations. J. Leukoc. Biol. 56: 278–288; 1994.