Depression is common in patients with neurologic disorders such as Alzheimer disease, stroke, Parkinson disease, and multiple sclerosis. Diagnosing depression in the context of neurologic disease is challenging, given the overlap between many signs and symptoms of depression with those of the neurologic disorders. Cognitive impairment further complicates diagnostic evaluation. The etiology of depression in these patients is not well understood and variously has been attributed to emotional reaction to the diagnosis or disability associated with the neurologic condition, the anatomical and/or neurochemical outcomes of neurodegeneration, and the influence of other disease factors. Beyond the inherent burden depression places on patients and caregivers, it increases cognitive and functional disability and, depending on the neurologic disorder, poorer treatment adherence and recovery, earlier institutionalization, and increased suicide risk. Few controlled antidepressant trials are available to guide treatment. In the absence of validated diagnostic guidelines for depression in each neurologic condition, clinicians are urged to remain vigilant for this treatable comorbidity. Although more controlled trials clearly are needed, existing studies suggest that depression in patients with neurologic disorders responds to antidepressant medication and, in some disorders, to psychotherapeutic approaches. Investigating the neuroanatomical and neurochemical correlates of depression comorbid with neurologic conditions also may clarify depression etiology and treatment in the general population.