Human immunodeficiency virus type 1 (HIV-1) infection causes progressive and ultimately profound immunosuppression. Initially, however, infection is associated with vigorous virus-specific immune responses, including both neutralizing antibodies and cytotoxic T lymphocytes (CTLs). Although the host immune response is ultimately unable to eliminate the virus, experimental data suggest that these immune responses help to inhibit virus replication during the prolonged asymptomatic phase of illness. A number of mechanisms have been proposed to contribute to viral persistence in infected persons, among them direct immunosuppressive effects of the virus; defects in antigen presentation; down-modulation of human leukocyte antigens (HLA); clonal deletion of existing immune responses; sequence variation leading to immune escape; and decreased T-helper cell function. The rationale supporting the use of vaccine therapy in HIV-1 infection is based on the hypothesis that viral persistence is due to an inadequate immune response generated by natural infection and that the immune system can be induced to generate more effective immunoregulatory responses by vaccination. Potential mechanisms by which this might occur include enhanced clearance of circulating virus, enhanced recognition of virus variants, enhanced presentation of viral antigens to the immune system, and increased regional T-cell help. A number of protocols evaluating vaccine therapy in HIV-1 infection are presently under way, the results of which should facilitate rational decisions regarding the use of this approach in HIV-1-infected persons.