Opioids have long been the mainstay of pain control for patients with cancer; however, their use in patients with chronic, moderate to severe pain has increased greatly in the past decade. The risk of drug-drug interactions (DDIs) is a concern with all medications, but is of particular concern in patients using opioids. Most opioids are metabolized via the cytochrome P450 enzyme system, the same system that metabolizes more than half of all prescription medications. Pharmacokinetic (PK) DDIs are those in which a drug causes a change in the absorption, distribution, metabolism, and/or elimination of another drug. PK DDIs involving opioids may result in reduced analgesic efficacy or toxicity of the opioid. Pharmacodynamic DDIs result when 2 drugs are coadministered and the concentration-response curve of 1 or both drugs is altered without a change in PK. The risk of DDIs in patients receiving opioids is particularly worrisome in those with comorbidities and those taking numerous medications. Given the high rates of polypharmacy in the elderly population, clinicians should use caution when prescribing opioids, and perhaps avoid certain opioids. DDIs can result in significant morbidity and mortality, primarily through overdosing or undertreatment, and are associated with increased healthcare utilization and costs. Clinicians often underestimate the risk of DDIs in patients using opioids. Comprehensive studies of real-world opioid utilization patterns are needed to determine the quantitative impact of opioid DDIs.