Restless legs syndrome (RLS) is a common disorder that can have a considerable impact on a patient’s functioning and quality of life. The pharmacologic armamentarium for RLS contains dopamine agonists, a-2d ligands, and opioids, among other agents. Each of these types of drugs has strengths and limitations, and treatment selection should be based on the frequency of RLS symptoms and any accompanying pain. Dopaminergic augmentation, which exacerbates RLS symptoms, is the most common and challenging side effect of long-term RLS treatment with dopamine agonists and requires special clinical consideration. Iron status is also important to the effective management of RLS.