Chronic pain, often defined as pain lasting longer than 3 months or past the time of normal tissue healing, is extremely common. According to a recent Institute of Medicine report, up to one-third of U.S. adults report chronic pain. Chronic pain is a major cause of decreased quality of life and disability and is often refractory to treatment. There has been a dramatic increase over the past 10 to 20 years in the prescription of opioid medications for chronic pain, despite limited evidence showing long-term beneficial effects. In addition, accumulating evidence indicates that prescription opioids may be associated with important harms, including accidental overdose, abuse, addiction, diversion, and accidents involving injuries (such as falls and motor vehicle accidents). Perhaps of most concern is the dramatic increase in overdose deaths associated with opioids. In 2011, there were 16,917 fatal overdoses involving prescription opioids. Prescription opioid misuse and abuse resulted in almost 660,000 emergency department visits in 2010, over twice as many as in 2004. Substance abuse treatment admissions for opiates other than heroin increased more than six-fold from 1999 to 2009. Opioids are also associated with adverse effects such as constipation, nausea, and sedation. Finally, data indicate potential associations between long-term opioid therapy and other harms, such as adverse endocrinological effects and hyperalgesia. These data underscore the complexity of clinical decisionmaking around long-term opioid therapy, which requires individualized assessments of the balance between benefits and harms; appropriate opioid selection, dose initiation, and titration strategies; integration of risk assessment and mitigation strategies; and consideration of the use of alternative, nonopioid therapies. Risk mitigation strategies that have been suggested for patients prescribed long-term opioids include use of opioid medication agreements, application of dose thresholds that warrant increased caution, regular clinical followup and monitoring, urine drug screens, use of abuse- deterrent opioid formulations, and use of data from prescription drug monitoring programs. Understanding benefits and harms of long-term opioid therapy for chronic pain is a challenge because effects may vary depending on patient characteristics (e.g., age, sex, pain condition, psychosocial factors, comorbidities), opioid characteristics (e.g., specific opioid, short- versus long-acting opioid, mode of administration, dose), dosing strategies (e.g., round-the-clock versus as-needed dosing, application of dose thresholds), concomitant therapies (e.g., use of benzodiazepines or other drugs that may interact with opioids), and characteristics of the clinical setting. The purpose of this report is to systematically review the current evidence on long-term opioid therapy for chronic pain.