While combination antiretroviral treatment has had a profound impact on the morbidity and mortality of human immunodeficiency virus (HIV) infection, the adherence demands of this therapy are high and failure to maintain viral suppression is common. Directly administered antiretroviral therapy (DAART) has garnered attention recently as a strategy to improve medication adherence and clinical outcomes in HIV-infected individuals. This review is intended to provide an update on the use of DAART and the challenges posed by this strategy, explore settings in which DAART may be used, discuss the role of antiretroviral regimens with improved pharmacokinetic features, and propose future directions for DAART strategies. DAART is modeled on directly observed therapy (DOT) for the treatment of tuberculosis. However, differences in curability, medication dosing frequency, duration of treatment, and the biologic dynamics of infection, pose unique challenges to DAART strategies. Numerous settings have been proposed for DAART, including community based outreach programs, prisons, long-term care facilities, substance abuse treatment sites, and resource-poor countries. Experience with DAART to date has been limited to pilot studies or retrospective comparisons. The prospect of simplified, once-daily antiretroviral therapy holds promise for DAART. However, improvements in antiretroviral therapy may also improve outcomes in patients taking therapy on a self-administered basis. Randomized controlled trials of DAART are needed before this strategy can be embraced in any setting. In future studies it will be important to compare DAART with self-administered therapy in terms of initial virologic and immunologic responses, durability of responses, the development of antiretroviral resistance, and cost effectiveness.