Depressive disorders are a prevalent comorbidity in restless legs syndrome (RLS). Although similar prevalence rates of comorbid depression can be found in other diseases, the association between RLS and depression is particularly complex due to the RLS-related sleep disorders. It is also clinically important that according to findings derived mainly from case studies many antidepressant agents can aggravate RLS symptoms. The presence of comorbid depression influences therapy outcome in general and should therefore be taken into account. So far, there is no evidence-based systematic research concerning diagnosis and treatment process, and no recommendations exist for the treatment of affective disorders in RLS. In the present work, the clinical relevance of depression in RLS and antidepressive treatment in RLS symptoms is discussed and a therapeutic algorithm (evidence level C) for the treatment of depression in RLS is provided.