Epidemiological studies report a 2- to 4-fold risk of a depressive disorder in patients with restless legs syndrome (RLS) compared with healthy controls. The high prevalence rates of depression in RLS indicate an association between the two disorders. Severe sleep disturbance due to the nightly occurrence of RLS symptoms is a common complaint of patients with moderate or severe RLS and may substantially contribute to the emergence of depressive symptoms. Difficulty in the diagnosis of a depressive disorder in patients with RLS may arise from the overlap of symptoms in the two disorders, as sleep-related complaints are frequent both in RLS and depression. The treatment of depression in RLS has some unique aspects, as several antidepressants have been reported to trigger or worsen RLS. To date, no studies have been published regarding the course of depression in untreated and treated patients with RLS. On the other hand, the presence of co-morbid depression can have a substantial impact on the global treatment outcome. In patients with co-morbid moderate/severe depression, antidepressant therapy in parallel with or shortly after commencing RLS treatment is usually necessary. Data from recent trials with dopamine receptor agonists indicate that mild to moderate depressive symptoms are often relieved with improvement of RLS symptoms.