HIV infection causes an acquired immunodeficiency, principally because of depletion of CD4 lymphocytes. The mechanism by which the virus depletes these cells, however, is not clearly understood. Since the virus predominantly infects CD4 lymphocytes in vivo, some have assumed that HIV replication directly kills the infected cells or that the anti-HIV immune response destroys them. However, a large number of studies do not support this concept. Rather, the data strongly indicate that CD4 lymphocyte depletion is by an indirect mechanism. Several theories on various direct and indirect mechanisms are reviewed. The most plausible mechanism, which is backed by in vivo data, involves the consequences of HIV contact with resting CD4 lymphocytes, which cannot support virus replication. HIV binding to, and signaling through, CD4 and chemokine receptor molecules on resting CD4 lymphocytes and other cell types [which extensively occurs as the rare, productively infected cells (ie: infected cells producing virus) migrate among other cells through the lymphoid tissues back into the blood] induces upregulation of L-selectin and Fas. When these resting, HIV-signaled CD4 cells return to the blood, they home very rapidly back to peripheral lymph nodes and axial bone marrow, and their disappearance from the blood is likely due to their leaving the circulatory system. Approximately one-half of these cells that have been induced by HIV to home to lymph nodes are subsequently induced into apoptosis during the process of trans-endothelial migration when secondary signals are received through various homing receptors. These cells are not making HIV, which would explain the observation that CD4 cells not making HIV are the predominant cells dying in the lymph nodes of HIV+ subjects. These studies indicate that the principal mechanism of CD4 T-cell depletion by HIV is due to its use of CD4 as its primary receptor and the signaling induced through this receptor on nonpermissive (resting) T-lymphocytes. This unique mechanism of viral pathogenesis, if correct, leads to the possibility that HIV might not cause depletion of CD4 lymphocytes if it used some other receptor to infect CD4 lymphocytes.