Restless legs syndrome (RLS) is a common neurological disorder in the United States. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and conserved biosynthetic and metabolic pathways, as well as its small size, ease of maintenance, speedy generation time and large brood size, C. elegans provides numerous advantages in studying RLS-associated gene-environment interactions. Here we will review current knowledge about RLS symptoms, pathology and treatments, and discuss the application of C. elegans in RLS study, including the worm homologous genes and methods that could be performed to advance the pathophysiology RLS.