Not all patients respond to effective and approved treatment interventions, and there has been growing recognition in the medical field of these “resistant” or refractory illnesses (eg, treatment-resistant depression, resistant hypertension). In the field of substance use disorders, there has not been an explicit acknowledgement of treatment-refractory addiction (TRA) despite substantial evidence that many patients do not respond to standard-of-care treatment interventions. This article provides a justification for TRA as a critically important condition to recognize and define. TRA is not conceptualized as a diagnosis, but as a signal that a current treatment approach has not worked. The article addresses areas in need of research and consensus in order to ensure the approach to TRA is uniform, thoughtfully addressed, and data-driven. By explicitly acknowledging TRA, clinicians, researchers, and patients and their families can begin to explore the unique features of this population and find ways in which substance use disorders for persons with TRA can be more effectively addressed, which in turn will help to expand remission for persons who suffer from these devastating conditions.