The current opioid crisis has brought renewed attention and scrutiny to opioid prescriptions. When patients receiving opioid therapy for pain engage in nonmedical opioid use (NMOU) or diversion, untoward consequences can occur. New evidence suggests that patients with cancer might be at a higher risk of NMOU than was previously thought, but clinical evidence still supports the use of opioid analgesics as the gold standard to treat cancer-related pain, creating a dilemma in patient management. Clinicians are encouraged to adopt a universal precautions approach to patients with cancer receiving opioids, which includes screening all patients; discussing the risks, benefits, adverse effects and alternatives of opioid therapy; and providing education on safe use, storage and disposal. Use of urine drug tests, prescription drug monitoring programmes and close observation of behaviours related to opioid use help to ensure treatment adherence, detect NMOU and support therapeutic decision-making. These measures can optimize the risk-benefit ratio while supporting safe opioid use. In this Review, we examine the role of opioids in cancer pain, the risk of substance use disorder and methods to achieve the right balance between the two in order to ensure safe opioid use.