Both chronic pain and prescription opioid abuse are prevalent and exact a high toll on patients, physicians, and society. Health care professionals must balance aggressive treatment of chronic pain with the need to minimize the risks of opioid abuse, misuse, and diversion. A thorough, ongoing assessment can help fashion a multimodal therapeutic plan, stratify patients by risk, and identify those who may exhibit aberrant behaviors after receiving opioid therapy. Appropriate safeguards (eg, urine drug screens, pill counts) may be used when necessary. Because not all aberrant behaviors have the same origins or implications, physicians must consider a differential diagnosis and tailor therapy accordingly. Opioid formulations designed to deter and resist abuse are currently in late-stage clinical development and address some but not all aspects of inappropriate opioid use. By incorporating physical and pharmacological barriers to obtaining the euphoric effects of opioids, these novel formulations may minimize problematic opioid use. The formulations use a variety of strategies, for example, combining opioids with naltrexone or niacin or incorporating the opioid in a high-viscosity matrix designed to resist physical and chemical extraction. Nonopioid medications as well as cognitive, behavioral, and interventional techniques should be considered for all patients with chronic pain, particularly for those who are unable to safely take their opioids in a structured fashion. The aim of this article was to help physicians prescribe opioid medications safely and successfully to patients who need them. A PubMed literature search was conducted using the keywords risk management, assessment, aberrant behavior, addiction, prescription abuse, and abuse-deterrent.