The past decade has seen an explosion of interest in both idiopathic and secondary restless legs syndrome (RLS). Secondary RLS occurs in patients with uremia, pregnancy, and iron deficiency. Patients experience an irresistible urge to move the legs that is worse during inactivity and at night. RLS affects 6.6% to 62% of patients on long-term dialysis therapy and is associated with a greater mortality risk. The wide range of reported prevalence is explained in part by variations in methods of diagnosis. The International Restless Legs Syndrome Study Group defined diagnostic criteria that have improved the quality of RLS research. Advanced neurological imaging techniques suggest the pathophysiological state of idiopathic RLS involves dysfunction of subcortical areas of the brain. Dopaminergic pathways and neuronal iron handling have been implicated. Limited studies of patients with uremic RLS suggested similar mechanisms, but anemia, hyperphosphatemia, and psychological factors also may have a role. The few clinical trials in uremic RLS suggest that treatment should involve the reduction of potential exacerbating agents (tricyclic antidepressants, selective serotonin uptake inhibitors, lithium, and dopamine antagonists), correction of anemia (with erythropoietin and iron), and use of levodopa or dopamine agonists. Other agents shown to be of benefit in idiopathic RLS can be tried, but may be limited by side effects in patients with uremia (benzodiazepines, opioids, gabapentin, carbamazepine, and clonidine). Symptoms of uremic RLS will disappear within a few weeks of successful renal transplantation. The progress made to date in unraveling the pathophysiological state of uremic RLS should stimulate additional research toward targeted therapy.