Background <p>Restless legs syndrome (RLS) is a common sleep disorder characterized by an irresistible urge to move the legs. Symptoms predominate in the evening and cause significant circadian rhythm interruptions that impact sleep and quality of life, leading to decreased work productivity, anxiety, and depression. Some patients improve with oral medications, but many experience treatment-refractory symptoms, whether from lack of efficacy or intolerable cognitive or behavioral side effects. Emerging evidence suggests that diverse neuromodulation modalities could provide a novel circuit-based therapy option for patients with treatment-refractory RLS. Given its prevalence, most of these reports arise as serendipitous observations of improved RLS symptoms when it is comorbid with an approved indication for neuromodulation, such as chronic neuropathic pain or a movement disorder. More recent work has begun investigating neuromodulation, including spinal cord stimulation, for primary idiopathic RLS. </p> Methods <p>Here we performed a PRISMA systematic review identifying 120 articles utilizing spinal cord stimulation, deep brain stimulation, transcranial magnetic stimulation, vagal nerve stimulation, and other modalities. Among these, we summarize findings from 54 studies that met our specific inclusion criteria and suggest potential mechanisms, such as spinal cord hyperexcitability, for neuromodulation of RLS symptoms. </p> Results <p>Interestingly, the amount and duration of RLS improvement seems to correlate with the invasiveness of the neuromodulation modality. Spinal cord stimulation has demonstrated more consistent, promising results with greater magnitude of IRLS Score improvement compared to the other modalities. </p> Conclusion <p>Prospective, multi-institutional trials are needed to evaluate whether various neuromodulation strategies can impact debilitating symptoms from treatment-refractory RLS, and rigorous analysis should be conducted to identify the most effective modalities.</p>