The effective treatment of depression in the elderly is complicated by a number of factors. The true prevalence of treatment-resistant depression in elders has been estimated to range from 18 to 40%. Biologic changes that occur as a consequence of normal aging may contribute significantly to treatment difficulties and intolerance or ineffectiveness, especially if not fully appreciated. These changes are briefly reviewed in this chapter. The relationship of cognitive functioning to depression is complex. The management of resistant depression in elderly patients remains a clinical challenge. Age-related social, biologic, and medical complications create challenges that differ from the treatment of younger individuals. Confronted with an apparently treatment-resistant elderly patient, management should proceed in a logical stepwise manner. In patients with complex medication histories, it is often helpful to prepare a chronological summary of the treatment as far as records or memories permit.