Advances in antiretroviral therapy have resulted in significant improvement in virological markers and clinical end points. However, studies have demonstrated that HIV can be recovered from patients in whom HIV RNA has been undetectable for prolonged periods of time, suggesting that the elimination half-life of latently infected cells may be longer than previously speculated. When used in the appropriate setting, cytoreductive agents may help expedite the elimination of the long-lived viral reservoir, and result in shorter administration of antiviral agents. In this article we discuss the potential use of cytoreductive agents as adjunctive therapy to antiretrovirals. In addition, we review those agents most likely to impact the viral reservoir and describe ongoing clinical trials designed to define the effect of cytoreductive therapy on those reservoirs. If a positive effect is demonstrated, these agents could ultimately be a powerful addition to the potent drugs currently being used to block HIV replication.