The concept of treatment-refractory addiction, proposed by Eric Strain in this edition of the Journal, has the potential to invigorate the field of addiction treatment and research by focusing on a phenomenon that is familiar to any clinician treating patients with substance use disorders, namely, the patient who does not experience sufficient improvement from standard treatments. An analogy is drawn to the concept of treatment-resistant depression and the STAR*D study, which demonstrated an algorithmic approach to treatment, where if the first antidepressant medication tried did not result in remission from depression, subsequent trials of medications or cognitive behavioral therapy doubled the proportion of patients achieving remission. Recognizing treatment-refractory addiction challenges our field to develop analogous, stepwise, algorithmic approaches to treatment of substance use disorders, moving away from siloed treatment programs toward integrated treatment systems where alternative treatments are available, offering the kind of personalized, tailored forms of care used in the treatment of most other chronic illnesses. Like in STAR*D, research could focus on samples of patients who have not benefitted from initial trials of standard addiction treatments, addressing the key clinical question of what to do next when previous treatments fail.