This article briefly presents one approach to conceptualizing known and suspected risk factors for co-morbid psychiatric disorder in epilepsy. The utility of this model is then reviewed by examining selected neurobiologic, psychosocial, and iatrogenic risk factors for a common co-morbid psychiatric disorder, interictal depression. Finally, data are presented concerning the rates of current and lifetime mood disorders among a sample of 76 patients with chronic complex partial seizures, the degree to which co-morbid depression has been recognized and treated in chronic epilepsy, and the health-related quality of life status associated with current and past mood disorders. Finally, these findings are related to the larger literature concerned with the recognition and treatment of depression.