To review the literature on restless legs syndrome (RLS), periodic limb movements in sleep, and depression. Literature review. N/A. We conducted a comprehensive review of the literature searching for publications that included data on depression or antidepressants and RLS or periodic limb movements in sleep. Sixtytwo relevant literature references were found and reviewed. Four population-based studies and 9 clinical studies reported significantly higher rates of depression symptoms in individuals with RLS than in controls. Conversely, the prevalence of RLS in patients presenting with depression was reported as elevated in 2 studies. Conflicting data were found regarding the effect of antidepressants on the sensory symptoms of RLS. In contrast, several studies have found that selective serotonin reuptake inhibitor antidepressant use is associated with increased periodic limb movements in sleep. Depression symptoms are common in adults with RLS. However, the relationship appears complex, with overlap between RLSand depression-related symptoms confounding the issue. Given what is known at this time, we propose a specific treatment approach to patients with RLS and depression symptoms.