The concept that HIV causes AIDS only by directly killing CD4 cells has been questioned by a number of investigators. There has been experimental support for a number of indirect mechanisms such as apoptosis, anergy, superantigen-induced cell proliferation and depletion, defective signaling, molecular mimicry, and autoimmunity. In this article we review the available evidence in support of these theories and suggest that in spite of their apparent differences, signaling by HIV through the T cell receptor could initiate the markedly different responses of activation, anergy, and apoptosis. However, the unifying mechanism as to how this is achieved remains unclear. It is likely that more than one of these mechanisms are involved in CD4 cell depletion during different phases of the disease. Understanding these mechanisms and their role in HIV pathogenesis would be important in new vaccine and therapeutic approaches.