Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration that may be related to genetically determined dysregulation of iron transport across the blood-brain barrier. Dopamine agonists (DAs) have been considered the first-line therapy, but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. Opioids can be considered as an alternative therapy, particularly in patients with DA-related augmentation. In more severe cases, a combination therapy may be required. Intravenous iron therapy may be considered on those patients with refractory RLS.