An epidemic of drug overdose deaths has led to calls for programs and policies to limit misuse and diversion of opioid medications. Any parallel call to consider the risk of iatrogenic addiction when treating pain has been muted in comparison. We have moved beyond questions of nonmedical use, abuse, and diversion to highlight the role of prescription opioids in causing addiction even when prescribed and used appropriately. Unfortunately, current evidence is insufficient, and a rapid expansion of longitudinal research is urgently needed to guide clinicians in balancing the need for opioids with the risk of adverse consequences. Meanwhile, medical education should place greater emphasis on the abuse liability of prescription opioids, and providers should endeavor to attenuate risk when possible.