The risk of depression is increased in chronic neurologic illness and can adversely affect the course of disease. Recent literature is reviewed for depression in stroke, epilepsy, and multiple sclerosis. Depression can share pathophysiologic aspects of the comorbid illness, such as neurotransmitter pathway disturbances, hypothalamus-pituitary-adrenal pathway disturbances, and changes in immunologic function. Depression also can be a psychologic reaction to the burden of the neurologic condition. Risk factors for development of depression are reviewed. Depression and other medical conditions can have shared symptoms (eg, fatigue, psychomotor retardation) that can complicate the diagnosis of depression in neurologic illness. Proper selection of antidepressant treatment is necessary to avoid worsening the neurologic disorder.