Opioids are commonly used to manage pain in patients with cancer and those near the end of life. Although opioids offer many therapeutic benefits, they are also a known high-risk medication. Deaths due to inadvertent opioid overdose are a major patient safety issue in ambulatory care, and this review sought to quantify how often opioids were implicated in adverse drug events in oncology and palliative care patients. Despite a broad literature search, the authors identified only a few relevant studies, most of which examined errors associated with opioid prescribing in hospitalized patients. As a result, it was not possible to estimate the incidence of opioid-related medication errors in this population. This lack of data hinders better understanding of the balance between risks and benefits of opioids in ambulatory care patients, which is very important given how frequently opioids are used for cancer pain. The AHRQ Health Care Innovations Exchange offers tools for organizations seeking to optimize opioid prescribing. A WebM&M commentary discussed a case of a death due to an unintentional opioid overdose.