Most pharmaceutical opioids are used to treat pain, and they have been demonstrated to be effective medications for many. Their abuse and misuse pose significant public health concerns in the USA. Research has provided much insight into the prevalence, scope, and drivers of opioid abuse, but a holistic understanding is limited by a lack of available data regarding key aspects of this public health problem. Twelve data gaps were revealed during the creation of a systems-level computer model of medical use, diversion, nonmedical use, and the adverse outcomes associated with opioid analgesics in the USA. Data specific to these gaps would enhance the validity and real-world applications of systems-level models of this public health problem and would increase understanding of the complex system in which use and abuse occur. This paper provides an overview of these gaps, argues for the importance of closing them, and provides specific recommendations for future data collection efforts.