Prescription opioid use for relief of noncancer pain has risen dramatically in the last 15 years, contributing to a quadrupling of opioid overdoses and prescription opioid-related deaths. This crisis is resulting in heightened attention by health care professionals and organizations, law enforcement, and the government. In this article, I highlight key topics in the management of patients using opioids (or potentially needing opioids) in outpatient clinical practice; federal and state law enforcement actions regarding physicians' illegal prescribing of opioids; multimodal approaches to pain control; nonmedication management of pain; response strategies when suspecting a patient of diverting or misusing opioids; and warning signs for abuse or diversion. For those patients for whom opioids are appropriate, I describe key elements for prescribing, including documentation of a detailed history and examination, appropriate evaluation to arrive at a specific diagnosis, individualizing management, and ongoing monitoring (including the use of urine drug screening and a prescription drug monitoring program). In addition to individual action, when possible, the initiation of systemwide and clinicwide safe prescribing practices supports the physician and patient such that the patient's well-being is at the heart of all pain management decisions. Physicians are encouraged to further educate themselves to treat pain safely and effectively; to screen patients for opioid use disorder and, when diagnosed, to connect them with evidence-based treatment; and to follow Centers for Disease Control and Prevention guidelines whenever possible.