Achieving the goal of quantitatively improving the quality and effectiveness of health care for all Americans requires both knowledge and tools. Although medical researchers have demonstrated many efficacious medical treatments to improve health outcomes, a recent Institute of Medicine report identified a disquieting discrepancy between present treatment success rates and those thought to be achievable. This gap has been attributed partly to barriers that providers face in implementing best practice guidelines. Patients' adherence to treatment, however, provides an additional explanation for the incongruity between recommended treatment and actual treatment outcomes. Poor medication adherence is relatively common. Studies have shown consistently that 20 to 30 percent of medication prescriptions are never filled and that, on average, 50 percent of medications for chronic disease are not taken as prescribed. This lack of adherence to medications is not only prevalent, but also has dramatic effects on individual and population-level health. Nonadherence has been estimated to cost the U.S. health care system between $100 billion and $289 billion annually in direct costs. Strong evidence suggests that benefits attributable to improved self-management of chronic diseases could result in a cost-to-savings ratio of approximately 1:10. Medication adherence is defined as "the extent to which patients take medication as prescribed by their health care providers." Medication adherence refers to the patient's conformance with the provider's recommendation with respect to timing, dosage, and frequency of medication taking during the prescribed length of time. In contrast, persistence refers to the act of continuing the treatment for the prescribed duration and may be defined as the total length of time a patient takes a medication, demarcated by the time between first and last dose. Health outcomes may be improved by helping patients better adhere to and persist with recommended treatment, in much the same sense that such outcomes may be improved by enhancing provider implementation of best practice guidelines. This review seeks to synthesize evidence regarding the efficacy and effectiveness of interventions to improve medication adherence among adults across a broad array of chronic conditions. This report is part of a larger initiative, the Closing the Quality Gap: Revisiting the State of the Science series. This series continues to summarize evidence on means to improve quality of care, but it focuses on selected settings, interventions, and clinical conditions. Our report addresses the comparative effectiveness of adherence intervention strategies, one keystone to improving the gap between potential and realized quality health care. The five Key Questions (KQs) that are the focus of this review are: KQ 1: a. Among patients with chronic diseases with self-administered medication prescribed by a provider, what is the comparative effectiveness of interventions aimed at patients, providers, systems, and combinations of audiences in improving medication adherence? b. Is improved medication adherence associated with improvement in patient outcomes? KQ 2: a. Among patients with chronic diseases with self-administered medication prescribed by a provider, what is the comparative effectiveness of policy interventions in improving medication adherence? b. Is improved medication adherence associated with improvement in patient outcomes? KQ 3: a. How do medication-adherence intervention characteristics (e.g., mode of delivery, intervention target, intensity) vary? b. To what extent do the effects of adherence interventions vary based upon their characteristics? KQ 4: To what extent do the effects of adherence interventions vary based on differences in vulnerable populations? KQ 5: What unintended consequences are associated with interventions to improve medication adherence?