Although treatment-refractory patients are well known to clinicians, refractory depression has received little empirical attention. Nonetheless, useful assessment and treatment strategies are available. First, it is important to determine whether a patient is truly treatment-refractory or simply has received inadequate treatment. Failure to provide adequate doses of medication for adequate periods of time is perhaps the most common cause of apparent treatment resistance. Other factors that may contribute to apparent treatment resistance are undiagnosed medical conditions, unrecognized depression subtypes, and unrecognized comorbid Axis I and II disorders. It is particularly important to detect the presence of "secret" comorbid disorders, which often go undiagnosed and contribute to refractory depression. Once the clinician has determined that a patient is truly treatment-refractory, many treatment approaches can be tried, including augmentation with lithium and perhaps other agents, combining antidepressants, and switching antidepressants. A modified treatment approach should be used for psychotic depression and perhaps for other depression subtypes as well (such as bipolar depression and atypical depression). Similarly, the depression associated with borderline personality disorder may best respond to a modified treatment approach. Finally, it is important to consider combining somatic treatments with psychosocial treatments in treating refractory patients.