After CD4+ T lymphocytes, mononuclear phagocytes were demonstrated to be infected in vivo and infectable in vitro by HIV-1. Unlike T cells, they are relatively resistant to the cytopathic effect of the virus therefore resulting in a persistent state of infection oscillating from latency to active virion production. In addition, macrophages can bud and accumulated ex novo produced virions in intracellular vacuoles of debated nature, a feature that has generated the so-called "Trojan horse" hypothesis on the role of these cells in HIV infection. In this scenario, we have recently observed that polarization of monocyte-derived macrophages (MDM) into classically activated (M1) or alternatively activated (M2a) cells by their “pulsed” stimulation with either TNF-α plus IFN-γ or IL-4, respectively, results in the inhibition of virus replication likely by different mechanisms. While M1-polarization acts at an early, pre-integration level in the virus life cycle, M2a-MDM appear restricted by post-integration mechanisms under intense investigation (E. Cassol, J Immunol. 182: 6237, 2009). Furthermore, M2a cells also express high levels of DC-SIGN that, conversely, facilitate infection and cell-mediated transmission of HIV-1 to CD4+ T cells. Since tissue macrophages, unlike dendritic cells, are mostly residential, M2a-driven DC-SIGN expression may play an important role in the local spreading of infection in mucosal rather than lymphatic tissues. In conclusion, macrophage polarization in vivo is likely to span a spectrum of activated phenotypes that may change their state of permissiveness to infection and profoundly influence their capacity to propagate HIV-1 to neighboring CD4+ cells.