Complex treatment schedules for human immunodeficiency virus (HIV) disease, which can have a high pill burden and can include multiple daily doses, in addition to the adverse effects that the medications can cause, may reduce patient adherence to therapy. Reduced adherence prevents achievement of the desired goal of full suppression of HIV replication, and it also promotes the development of drug-resistant strains of HIV. Thus, the focus of treatment has shifted toward the use of simpler regimens. A major strategy is the development of medications and regimens for management of HIV infection that can be taken once per day. The goal of such a strategy is to improve convenience and optimize adherence, which is critical to maximizing the likelihood of sustained virologic response. Several studies involving regimens with once-daily dosing, which have involved both available agents and agents in development, have yielded promising results. In comparison with standard regimens, which involve dosing 2 or 3 times daily, the regimens with once-daily dosing improved tolerability while maintaining efficacy and safety. The results are expected to increase adherence rates among patients, reduce the incidence of antiretroviral-resistant variants of HIV, and improve the clinical outcomes during a prolonged treatment course.