Increased abuse and diversion of prescription opioids has been a consequence of the increased availability of opioids to address the widespread problem of undertreated pain. Opioid risk management refers to the effort to minimize harms associated with opioid therapy while maintaining appropriate access to therapy. Management of these linked public health issues requires a coordinated and balanced effort among a disparate group of stakeholders at the federal, state, industry, practitioner, and patient levels. This paper reviews the principles of opioid risk management by examining the epidemiology of prescription opioid abuse in the United States; identifying key stakeholders involved in opioid risk management and their responsibilities for managing or monitoring opioid abuse and diversion; and summarizing the mechanisms currently used to monitor and address prescription opioid abuse. Limitations of current approaches, and emerging directions in opioid risk management, are also presented.