Abstract Variety and magnitude of therapy-resistant depressive disorders continue to be of urgent interest to clinicians and researchers. In 1973, the section on pharmacopsychiatry of the World Psychiatric Association (WPA) held a symposium on Therapy-Resistant Depression, in Basel, Switzerland. 1 Clinical typology, biochemistry, genetics, therapeutic differential criteria, and theoretic considerations were explored to determine their role in resistance to treatment. 2 There were convincing indications that the rate of therapeutic failures in terms of ultimate outcome is considerable. Methodologic problems still prevail in distinguishing between poor results due to inadequate treatment and therapeutic failures after systematic administration of appropriate treatment modalities. In the Basel symposium, Kelly advocated limbic leucotomy as a promising step after every other method of treatment has failed. 3 Similarly, in a recent paper on the treatment of affective disorders, Shaw included stereotactic tractotomy as a treatment of choice when other treatment had failed. 4 It is nevertheless not generally accepted that a full battery of therapeutic methods must include brain surgical procedures. At any rate, the rationale for pharmacotherapy and electroconvulsive therapy (ECT) rests on the assumption that biochemical deficiencies are responsible for depressive syndromes and can be corrected by these treatments. I want to base my brief presentation on three patient profiles that demonstrate some principal aspects of resistance to treatment. I have treated each patient for several years, as had other psychiatrists before me, and, in one case, after me. These patients are by no means atypical, but on the contrary represent a rank and file of patients with affective illness. Yet for reasons that have to do with research design, they are most unlikely to be covered in reported clinical investigations.