Antigen presenting cell (APC) function is central to the development of an effective anti-viral immune response. Among APC, monocytes, macrophages and dendritic cells (DC) form the principal non-T cell compartment involved in in vivo HIV infection, and these cells play important and well-established roles in multiple aspects of viral pathogenesis. HIV infection may result in APC defects, which could ultimately contribute to the loss of CD4+ T cell responses observed early in HIV infection, when the CD4+ T cell number is still within the normal range. Extensive in vitro studies have demonstrated that the envelope glycoproteins of HIV-1 exert profound influences on various cell populations of the immune system, including hematopoietic progenitors, T and B lymphocytes, monocytes/ macrophages and DC, as well as on neuronal cells. The demonstration of the presence of envelope proteins both free in the circulation and bound to the surface of CD4+ cells suggests that gp120 interactions with non-infected cells can influence cellular functions in vivo, thus contributing to the immunopathogenesis of AIDS. This paper provides an overview of the present knowledge on gp120 binding, signal transduction triggering and interference with macrophage and DC functions and it highlights the importance of this interaction in the pathogenesis of AIDS.