During the past decade, combined highly active antiretroviral therapy (HAART) consisting of the nucleoside, non-nucleoside and protease inhibitors has improved the outlook for HIV-infected individuals. However, despite the clinical improvement associated with HAART, current antiviral drug regimens are not able to eradicate HIV due to the persistence of virus in cellular reservoirs (predominantly long-lived memory CD4+ T cells and cells of the macrophage lineage) and anatomical sanctuary sites (brain and possibly testis). Detailed knowledge of viral reservoirs is essential for the effective design of therapeutic eradication strategies such as immunostimulation of virus-persistent reservoirs and better penetration of antiretroviral drugs into sanctuary sites. The recent therapeutic approaches undertaken thus far, including immune activation, intensification protocols combined with HAART, antiretroviral treatment during seroconversion, structured treatment interruptions, activation of latent infection or targeted killing of viral reservoirs have failed to completely eradicate the virus. This review provides an evaluation of the current HAART regimens exploring the reasons for their inability to eradicate HIV from cellular reservoirs and anatomical sanctuary sites. We also provide examples of therapeutic strategies that aim to eradicate the virus, flush out reservoirs and increase antiretroviral drug concentration in these cells and tissue compartments.