Twenty years into the HIV epidemic, highly active antiretroviral therapy (HAART) represents the only effective intervention to control HIV-1 disease progression. However, the prospect of life-long treatment with HAART is challenging given cumulative drug toxicities, difficulties with adherence to complicated regimens and the looming emergence of drug-resistant viruses. The challenges are even greater in resource-poor settings where costs and logistical problems with delivery represent formidable obstacles. Alternative approaches to long-term control of viral replication and disease progression are clearly needed.