PURPOSE OF REVIEW: Highly active antiretroviral therapy has dramatically improved the outlook for HIV-infected patients. However, there are a number of major challenges in administering this therapy, including the high cost, potential toxicities, drug resistance, and the need for near-perfect adherence. There thus remains a need to develop immune-based therapeutic approaches that may help augment the benefits of highly active antiretroviral therapy or spare requirements for life-long dependence on continuous therapy. RECENT FINDINGS: Basic science studies have improved our understanding of the complex immune response necessary to control HIV viremia. The improved tolerability and feasibility of highly active antiretroviral therapy regimens has optimized immunological conditions for testing therapeutic immunization, while also creating a challenge in terms of trial designs that allow researchers to distinguish between the immunological benefits of immune-based adjuvants in combination with highly active antiretroviral therapy versus the therapy alone. Some recent studies have suggested that therapeutic immunization has the potential to modify the natural history of HIV disease favorably, but there are discordant results between studies as well as between surrogate markers and actual clinical outcomes within studies. SUMMARY: There are intriguing hints that therapeutic vaccination may play a role as the era of highly active antiretroviral therapy progresses, especially as new vaccine technologies with the potential to elicit clinically relevant HIV-specific neutralizing antibody and cytotoxic T-cell responses are developed further. Trial designs utilizing 'analytical treatment interruption' should provide a short-term assessment of whether immune-based interventions modify the host's ability to control viremia in the absence of highly active antiretroviral therapy.