Use of opioids for the treatment of pain is necessary for the majority of patients with advanced cancer, however its use has become challenging in the face of the opioid epidemic and the emerging evidence that patients with cancer are also at risk for nonmedical opioid use. This article proposes an assessment and treatment plan that incorporates universal screening with monitoring for all patients with cancer who are considered for opioid treatment to assess their risk for opioid misuse and harm. Timely identification with appropriate management, including referral of at-risk patients, will allow oncology professionals to optimize the risk-to-benefit and support the safe use of opioids for patients with cancer.