Background/Aims: Opioid substitution treatment (OST) improves outcomes in opioid dependence. However, controlled drugs used in treatment may be misused or diverted, resulting in negative treatment outcomes. This review defines a framework to assess the impact of misuse and diversion. Methods: A systematic review of published studies of misuse and diversion of OST medicines was completed; this evidence was paired with expert real-world experience to better understand the impact of misuse and diversion on the individual and on society. Results: Direct impact to the individual includes failure to progress in recovery and negative effects on health (overdose, health risks associated with injecting behaviour). Diversion of OST has impacts on a community that is beyond the intended OST recipient. The direct impact includes risk to others (unsupervised use; unintended exposure of children to diverted medication) and drug-related criminal behavior. The indirect impact includes the economic costs of untreated opioid dependence, crime and loss of productivity. Conclusion: While treatment for opioid dependence is essential and must be supported, it is vital to reduce misuse and diversion while ensuring the best possible care. Understanding the impact of OST misuse and diversion is key to defining strategies to address these issues.