OBJECTIVE: The authors' goal is to address the complex issue of treatment-refractory depression from a clinical perspective. DATA COLLECTION: They review the literature on the major clinical and methodological issues involved in the treatment and study of treatment- refractory depression as well as primary and tertiary care surveys of patients whose depression has not responded to treatment. FINDINGS: There are methodological problems in defining treatment-refractory depression and in the tertiary care surveys of treatment-refractory depression. The authors define treatment-refractory depression as primarily involving diagnostic-treatment variables rather than patient variables. They articulate these variable as a series of questions the clinician may consider when confronted with patients who are considered refractory: 1) Is the diagnosis correct? 2) Has the patient received adequate treatment? 3) Was a rational stepped-care approach used? 4) How was outcome measured? 5) Is there a coexisting medical or psychiatric disorder that interferes with response to treatment? and 6) Are there factors in the clinical setting that are interfering with treatment? CONCLUSIONS: The problem of treatment-refractory depression has to do primarily with the diagnostic-treatment process than with patient variables. This has a number of implications in the areas of training, education, research, and public health. The evidence indicates that improvements in the recognition and treatment of depression are needed.Abstract Teaser