Current antiretroviral therapy has had a significant impact on HIV associated morbidity and mortality. Despite these positive outcomes current antiretroviral regimens have significant deficiencies which include multiple drug-drug interactions, high pill burdens, and considerable financial expense. Perhaps the greatest shortcoming is the apparent inability of current therapy to disrupt low level viremia in certain cellular reservoirs despite maximal virologic control as determined by polymerase chain reaction detection. These drug-resilient reservoirs preclude the ability to discontinue antiretrovirals while maintaining viral control. Additionally, they may be responsible at least in part for the evolution of drug resistant variants. Various researchers have proposed that certain immune modulating agents known as virostatics (i.e., hydroxyurea (HU), mycophenolate mofetil (MMF), and cyclosporine (CSA)) may have some efficacy in managing HIV disease and/or disrupting resilient reservoirs. These agents may act by reducing the pool of activated CD4+ cells which are susceptible to infection thereby inhibiting the characteristic immune over-activation seen in most HIV infected patients. Virostatics have primarily been studied in patients with advanced HIV disease and as components of trials involving structured treatment interruptions. These trials have demonstrated conflicting results with regard to viral load and CD4+ cell counts as well as potential adverse effects including immune suppression. Before widespread use of these agents can be recommended, larger, well controlled trials will need to be conducted to determine which virostatic agents are appropriate for use in HIV infected patients and the most efficacious time course within which to initiate these agents.