Several studies on Restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that up to 60% report a positive family history. Investigations of single families with RLS have suggested an autosomal dominant mode of inheritance with variable expressivity, and some families show possible anticipation. At present, only one twin study is available, showing a high concordance rate (83.3%) between identical twins. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, but no significant findings have been reported. Genome-wide studies have been conducted to map genes that play a role in vulnerability to RLS. In a single French-Canadian family significant linkage was established on chromosome 12q. The susceptibility locus on chromosome 12q was not confirmed in two South Tyrolean families, or in our two Italian families. However, the efforts toward the identification of RLS genes must continue in order to obtain a better characterization of the syndrome and to identify new therapeutic strategies.