Due to the limited efficacy of the current antiretroviral drug regimens in completely eradicating HIV and reconstituting the immune system, AIDS research is turning toward immune-based therapy to complement highly active antiretroviral therapy. Here we review potential mechanisms of protective cellular immunity and current HIV-specific immune-based strategies and discuss the rationale for novel hypothetical immunologic approaches for modulation of host antiviral immunity. One of the mechanisms by which the immune system exerts antiviral effects is via leukocyte generation of anti-HIV factors. Recent observations in this area of research suggest that non-HIV antigens can stimulate the in vitro production of anti-HIV activity by leukocytes from healthy uninfected individuals and HIV-infected patients. These findings may provide insights for the design of novel therapeutic or prophylactic approaches, which might contribute to modulating immune system control of HIV infection.