One of the hallmarks of untreated HIV infection is a progressive loss of effective immunity to both HIV-associated and non-HIV antigens. Combination antiretroviral therapy can frequently control viral replication, resulting in variable levels of immune reconstitution, but has not resulted in restoration of effective immunity to the virus. Understanding the limitations of immune reconstitution following highly active antiretroviral therapy (HAART) and identifying approaches to enhance immunity in this context may not only improve outcome for patients with HIV infection but could also provide insight for immune reconstitution in other conditions associated with T cell depletion.