Estimates of adherence to long-term medication regimens range from 17% to 80%, and nonadherence (or nonpersistence) can lead to increased morbidity, mortality, and healthcare costs. Multifaceted interventions that target specific barriers to adherence are most effective, because they address the problems and reinforce positive behaviors. Providers must assess their patients’ understanding of the illness and its treatment, communicate the benefits of the treatment, assess their patients’ readiness to carry out the treatment plan, and discuss any barriers or obstacles to adherence that patients may have. A positive, supporting, and trusting relationship between patient and provider improves adherence. Individual patient factors also affect adherence. For example, conditions that impair cognition have a negative impact on adherence. Other factors—such as the lack of a support network, limited English proficiency, inability to obtain and pay for medications, or severe adverse effects or the fear of such effects—are all barriers to adherence. There are multiple reasons for nonadherence or nonpersistence; the solution needs to be tailored to the individual patient’s needs. To have an impact on adherence, healthcare providers must understand the barriers to adherence and the methods or tools needed to overcome them. This report describes the barriers to medication adherence and persistence and interventions that have been used to address them; it also identifies interventions and compliance aids that practitioners and organizations can implement.