Lidocaine and mexiletine are class 1B antiarrhythmic drugs that act on sodium channels. Lidocaine is also an important anesthetic and topical agent that is useful in the treatment of multiple pain disorders, and mexiletine is commonly used for neuropathic pain and myotonia. Both intravenous lidocaine and mexiletine are increasingly used to treat pain syndromes and appear to be particularly effective in neuropathic pain. This suggests a role for these agents in patients with headache disorders. This article describes the role of intravenous lidocaine and mexiletine in the management of headache and trigeminal autonomic cephalalgias based on the published literature to date and provides practical guidelines for their use.