In both clinical trials and clinical practice, nonadherence to medications is widespread among patients with chronic diseases. The shift to combination therapies for treating human immunodeficiency virus (HIV)-infected individuals has increased adherence challenges for both patients and health-care providers. Estimates of average rates of nonadherence to antiretroviral therapy range from 50% to 70%. Adherence rates of <80% are associated with detectable viremia in a majority of patients. The principal factors associated with nonadherence appear to be patient-related, including substance and alcohol abuse. However, other factors may also contribute, such as inconvenient dosing frequency, dietary restrictions, pill burden, and side effects; patient-health-care provider relationships; and the system of care. We discuss the major reasons reported by HIV-infected individuals for not taking their medications. Improving adherence probably requires clarifying the treatment regimen and tailoring it to patient lifestyles.