Antiretroviral therapy has dramatically improved the prognosis for many patients with HIV infection. For many patients who can navigate combinations of drugs and time their doses precisely, these drug regimens typically slow the progression of the disease and lengthen survival. But because these drug regimens are very complex, adherence—the degree to which patients follow medical advice in taking the prescribed drugs—is now a major determinant of HIV treatment success. This Issue Brief summarizes recent work on the effect of adherence on short-term outcomes, and the ability of providers to predict and estimate their patients’ adherence to therapy.