The most important traditional hypotheses of the pathogenesis of idiopathic restless legs syndrome (iRLS) involve dopaminergic dysfunction and iron deficiency. However, a possible role of other neurotransmitter or neuromodulators, mainly glutamate, gamma-hydroxybutyric acid (GABA), and adenosine have been suggested in recent reports. Moreover, iron deficiency in experimental models (which causes sensorimotor symptoms resembling those of RLS) is able to induce changes in dopaminergic, glutamatergic and adenosinergic neurotransmission, thus suggesting its crucial role in the pathogenesis of this disease. Relationship between iRLS and opiates, oxidative stress and nitric oxide, and with vitamin D deficiency has also been reported, although data regarding these variables should be considered as preliminary. In this review, we focus on studies relating to neurochemical findings in iRLS.